@article {pmid42429089,
year = {2026},
author = {Zhang, Z and Li, D and Liu, J and Lu, L and Cai, W and Yu, G},
title = {[Mechanism of Bushen Yijing Formula in improving cognitive function in Alzheimer's disease model mice].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {},
number = {},
pages = {1-12},
doi = {10.3724/zdxbyxb-2025-0747},
pmid = {42429089},
issn = {1008-9292},
abstract = {OBJECTIVES: To explore the mechanism of Bushen Yijing Formula (BSYJF) in the treatment of Alzheimer's disease (AD) through an integrated approach combining transcriptomics, network pharmacology, and molecular docking.

METHODS: Twelve amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice were randomly divided into normal control, model, and BSYJF groups. The treated group received daily intragastric administration of BSYJF for 12 consecutive weeks. Cognitive function and hippocampal amyloid β-protein (Aβ) deposition were assessed using behavioral tests and immunohisto-chemistry. Hippocampal tissues were subjected to transcriptomic sequencing to identify differentially expressed genes (DEGs). Functional enrichment analyses were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). In parallel, active compounds of BSYJF were screened via the TCMSP and PubChem databases, and AD-related targets were retrieved from GeneCards and other disease databases. Core targets were identified by intersecting these targets with transcriptomic DEGs. Molecular docking and molecular dynamics simulations were employed to evaluate binding affinity between active compounds and core targets, and qPCR was used to validate expression changes of core target genes.

RESULTS: BSYJF treatment improved cognitive function and reduced hippocampal Aβ deposition in APP/PS1 mice. Transcriptomic analysis revealed 73 DEGs between the model and BSYJF groups. GO analysis identified enrichment in 281 biological processes, 104 cellular components, and 120 molecular functions. KEGG analysis highlighted 110 pathways, and GSEA supplemented 322 enriched gene sets, many related to the immune system, neurodegenerative diseases, and signaling pathways such as Th17 cell differentiation and NF-κB. Integrated analysis with network pharmacology prioritized 10 core targets. Molecular docking and molecular dynamics simulations indicated strong structural stability and binding affinity of BSYJF bioactive constituents to these core targets. qPCR results confirmed that BSYJF downregulated the expression of Aurkb, Nr1i3, and Ttk, while upregulating Apob and Ces1d, consistent with the transcriptomic findings.

CONCLUSIONS: Transcriptomics, bioinformatics analysis, and animal experiments suggest that BSYJF may regulate immune-inflammatory responses and alleviate neuronal damage through a multi-component, multi-target, and multi-pathway approach, thereby improving cognitive function in AD model mice.},
}

@article {pmid42429504,
year = {2026},
author = {Lu, K and Lu, Y and Tang, R and Dong, X and Zhuang, P and Gao, Y and Cheng, M and Wang, Y and Wang, Y},
title = {Mechanisms of autophagy-lysosome pathway impairment in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261460879},
doi = {10.1177/13872877261460879},
pmid = {42429504},
issn = {1875-8908},
abstract = {The autophagy-lysosomal pathway is key for the removal of harmful substances in cells. This article integrates evidence that highlights the role of lysosomal function and the autophagy-lysosomal pathway in maintaining intracellular homeostasis and the effects of their dysfunction on protein secretion and metabolic disorders, leading to the pathogenesis of Alzheimer's disease (AD) and other tau diseases. Dysfunction of the autophagy-lysosomal pathway is believed to be the main factor leading to the accumulation of amyloid-β and tau proteins, which are also pathological features of AD. This article also discusses why autophagy is indispensable in the early to mature stages of neuronal development and how damage to the function of autophagy can cause neurodevelopmental abnormalities and neurodegenerative diseases. We also summarized the potential role of oligodendrocytes. We believe that its relationship with lysosomes can provide a new perspective and research direction for future research on neurodegenerative diseases. Autophagy-lysosomal pathway damage is considered to be a key factor in the pathology and diagnosis of multiple sclerosis, but we believe that the challenge associated with its transformation into clinical treatment is enormous. These findings suggest that enhancing or improving autophagy function may be an effective treatment method to alleviate the condition of AD patients, which can provide new strategies for clinical treatment and intervention of AD in the future.},
}

@article {pmid42430015,
year = {2026},
author = {Khodaei, M and Bidabad, B and Shiri, ME and Sedaghat, MK},
title = {Ricci Flow-Based Approach for Early Diagnosis of Alzheimer's Disease.},
journal = {Neuroinformatics},
volume = {24},
number = {3},
pages = {},
pmid = {42430015},
issn = {1559-0089},
mesh = {*Alzheimer Disease/diagnostic imaging ; Humans ; *Magnetic Resonance Imaging/methods ; Early Diagnosis ; *Hippocampus/diagnostic imaging/pathology ; Female ; Aged ; Male ; Discriminant Analysis ; *Image Interpretation, Computer-Assisted/methods ; Aged, 80 and over ; Imaging, Three-Dimensional/methods ; },
abstract = {Early diagnosis of Alzheimer's disease (AD) is increasingly important due to its rising prevalence and significant impact on individuals, families, and healthcare systems. Hippocampal atrophy is a well-established and significant biomarker for AD. Advanced techniques like MRI imaging and surface parameterization have shown considerable promise in improving the accuracy and speed of AD diagnosis. This study aims to utilize the Ricci flow method to map the 3D hippocampal surface to a 2D sphere and extract relevant features for early AD detection. The process involves several key steps: inputting an MRI scan and preprocessing to isolate the hippocampal surface, applying the Ricci flow to map this surface to a sphere, constructing a feature vector using Linear Discriminant Analysis (LDA) and Kernel LDA, and employing various classifiers to diagnose AD, with model evaluation based on the ADNI dataset. Experimental results reveal that combining Ricci flow-based feature extraction with Kernel LDA significantly improves diagnostic accuracy. The model achieves classification accuracies of 97.28% (NC/AD), 96.14% (NC/EMCI), 96.45% (NC/MCI), 94.83% (EMCI/LMCI), 95.84% (MCI/AD), and 95.37% (LMCI/AD). Additionally, it attains 93.65% and 92.30% accuracy in three-way and four-way classification tasks, respectively. These results outperform most reviewed studies and are comparable to others. This research highlights the potential of merging advanced 3D imaging techniques with mathematical models to enhance diagnostic precision, emphasizing the critical role of early detection in the effective treatment and management of Alzheimer's disease.},
}

*Alzheimer Disease/diagnostic imaging
Humans
*Magnetic Resonance Imaging/methods
Early Diagnosis
*Hippocampus/diagnostic imaging/pathology
Female
Aged
Male
Discriminant Analysis
*Image Interpretation, Computer-Assisted/methods
Aged, 80 and over
Imaging, Three-Dimensional/methods

@article {pmid42431348,
year = {2026},
author = {Ma, Q and Ding, Z and Wang, R and Jin, J and Wang, H and Li, Y and Liu, Z and Wang, X and Yin, T},
title = {40 Hz-rTMS modulates spike-LFP coupling and improves cognitive function in 5xFAD mice.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115909},
doi = {10.1016/j.expneurol.2026.115909},
pmid = {42431348},
issn = {1090-2430},
abstract = {OBJECTIVE: Spike-local field potential (LFP) coupling plays a pivotal role in mediating cross-scale neural communication. Although abnormal coupling has been reported in Alzheimer's disease (AD) models in vitro, in vivo evidence remains lacking. This study aimed to characterize in vivo spike-LFP coupling in 5XFAD mice and investigate whether 40 Hz repetitive transcranial magnetic stimulation (rTMS) can ameliorate related deficits.

METHODS: We performed chronic in vivo electrophysiological recordings of spikes and LFPs were performed in the hippocampal dentate gyrus (DG) via. Phase-locking and coherence analysis were employed to quantify spike-LFP coupling. Cognitive function was evaluated using the Y-maze, novel object recognition, and Morris water maze tasks. The correlation between spike-LFP coupling and cognitive performance was analyzed by the Spearman method.

RESULTS: In wild-type (WT) sham mice, DG spikes exhibited tightly confined phase preferences (θ oscillation: 108°-126°; high γ (Hγ) oscillation: 198°-216°). In contrast, 5XFAD mice displayed severely dispersed spike-phase distributions and reduced coupling intensity, with mean vector length decreasing by 19.90% (spike-θ) and 23.8% (spike-Hγ) compared with that in WT-sham controls. Following 14 consecutive days of 40 Hz rTMS intervention, 5XFAD mice exhibited significant increases in mean vector length (θ: +39.44%; Hγ: +31.47%) and normalized spike-LFP phase distributions. Notably, rTMS treatment also markedly rescued learning, memory, and cognitive flexibility in 5XFAD mice. Spike-LFP coupling strength was significantly correlated with learning and memory performance.

CONCLUSION: These preliminary findings suggest that 40 Hz rTMS modulates pathological spike-LFP coupling in 5XFAD mice, laying the groundwork for therapeutic exploration.},
}

@article {pmid42431472,
year = {2026},
author = {Kurz, CI and Tegethoff, P and Gelz, J and Gkempelsi, I and Hufnagel, A and Neziraj, F and Schuhbauer, P and Rahn, H and Boeck, M and Keidel, LF and Perneczky, R},
title = {The DECISION Study: Protocol for the Development and Internal Validation of a Multimodal Decision-Making Capacity Framework.},
journal = {Journal of clinical epidemiology},
volume = {},
number = {},
pages = {112417},
doi = {10.1016/j.jclinepi.2026.112417},
pmid = {42431472},
issn = {1878-5921},
abstract = {BACKGROUND: Decision-making capacity (DMC) is a prerequisite for valid informed consent, as well as being a key methodological requirement in clinical and epidemiological research. For individuals with neurocognitive disorders, DMC assessment is frequently based on subjective clinical judgement, with limited standardization and significant variability across settings. Current instruments are resource-intensive and not sufficiently adapted for stage-specific or real-world applications.

OBJECTIVE: To develop and internally validate a structured multimodal framework for assessing decision-making capacity in individuals across the Alzheimer's disease continuum.

METHODS: We propose a modular assessment framework that operationalizes the core domains of decision-making capacity: understanding, appreciation, reasoning and expression of choice. This is complemented by neuropsychological profiling, informant-based measures and structured decision scenarios. Internal validation will be performed against established functional reference standards, including the MacArthur Competence Assessment Tool for Treatment (MacCAT-T), while the Clinical Dementia Rating (CDR) will be used for disease characterization only. Primary analyses focus on feasibility, reliability, and criterion validity. Biomarkers and neuroimaging measures are examined as exploratory contextual correlates of decisional vulnerability and are not used to define decision-making capacity. The co-design approach thus integrates both patient and caregiver perspectives as well as clinician and expert input, with focus group interviews providing a complementary, structured format to capture interdisciplinary professional perspectives.

RESULTS: The protocol is designed to generate evidence regarding feasibility, reliability, and criterion validity of a multimodal DMC assessment framework. It provides standardized scoring and quantifiable outputs, as well as a basis for stage-sensitive interpretation. Exploratory analyses will further evaluate associations between functional decision-making capacity and markers of neurodegenerative disease burden. This methodological framework provides a standardized, reproducible approach to assessing decision-making capacity in cognitively vulnerable populations.

CONCLUSIONS: Developed within the German legal framework, it integrates cognitive, functional and contextual dimensions to support more transparent and quantifiable capacity assessment. Following external validation, the framework may inform future clinical studies, observational research, and ethically robust consent procedures in cognitively impaired populations.},
}

@article {pmid42432671,
year = {2026},
author = {Chen, F and Wang, L and Liu, H and Khan, Q and Tang, B and Bao, N},
title = {The role of AI-assisted drug repurposing in neurological disorders: a systematic review of validation strategies, challenges and opportunities.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04551-7},
pmid = {42432671},
issn = {1477-3155},
abstract = {Neurological disorders refer to a diverse group of conditions that affect the brain, peripheral nerves, and spinal cord and impair socioemotional, cognitive, motor, and sensory functions. Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are some of the well-known neurodegenerative diseases that affect millions of people worldwide. Despite the advanced technologies and nano-drug delivery systems, the success rate of developing drugs for neurological disorders is significantly low. Among several constraints, including gastrointestinal irritation, rapid metabolism, and low stability, the blood-brain barrier (BBB) emerges as one of the key challenges in the development and application of drugs against neurological disorders. These challenges necessitate innovative approaches to develop cost-effective therapeutic strategies. Drug repurposing, the discovery of new therapeutic benefits of existing drugs, is a promising drug discovery approach for discovering potential treatment options for complex neurological disorders. This review aims to explore the advanced and significant progress in drug repurposing for major neurological disorders, including MS, AD, PD, ALS, HD, stroke, and neuropsychiatric conditions. It places an explicit emphasis on discussing the potential role of artificial intelligence (AI)-assisted drug repurposing and understanding of the biological mechanisms in discovering new drugs for these neurological conditions. This also examines current challenges in drug repurposing and provides a critical review of the available opportunities and limitations in AI-assisted drug repurposing.},
}

@article {pmid42433215,
year = {2026},
author = {Cai, L and Zhao, X and Liao, C and Liu, Q and Hu, S and Huang, M},
title = {Efficacy and predictors of cognitive stimulation therapy combined with pharmacotherapy for mild-to-moderate Alzheimer's disease: a randomized controlled trial.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1840039},
pmid = {42433215},
issn = {1664-0640},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is associated with progressive cognitive decline, functional impairment, and reduced quality of life. Although pharmacological treatments such as cholinesterase inhibitors and memantine are commonly used, their clinical benefits remain limited and heterogeneous. Cognitive stimulation therapy (CST) may provide additional benefits when combined with standard pharmacotherapy. This randomized controlled trial (RCT) aimed to evaluate the clinical efficacy of modified CST combined with standard drug therapy on cognitive function, activities of daily living, and quality of life in patients with mild-to-moderate AD and to explore key predictors of CST efficacy using a multivariate regression model.

METHODS: This evaluator-blinded randomized controlled trial enrolled 80 patients with mild-to-moderate Alzheimer's disease (AD), who were randomly assigned in a 1:1 ratio to either the modified CST plus standard pharmacotherapy group (study group, n = 40) or the standard pharmacotherapy-alone group (control group, n = 40).The modified CST program comprised 14 weekly 45-minute sessions. The primary endpoint was the change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score from baseline to post-intervention. Secondary measures included the Activities of Daily Living (ADL) scale and the Quality of Life in Alzheimer's disease (QOL-AD) questionnaire. Data were analyzed using an intention-to-treat (ITT) approach. Independent predictors of treatment efficacy were identified using a two-stage screening strategy (univariate screening and stepwise regression).

RESULTS: A total of 75 patients completed the study, and 80 were included in the ITT analysis. After 14 weeks of intervention, baseline-adjusted ANCOVA showed that the study group had significantly better post-intervention ADAS-Cog scores than the control group. The adjusted mean difference in ADAS-Cog score was -3.28 points (95% CI: -3.72 to -2.83; P < 0.001), favoring the study group. Significant baseline-adjusted between-group differences were also observed for ADL (adjusted mean difference = -4.93, 95% CI: -8.39 to -1.47; P = 0.006) and QOL-AD (adjusted mean difference = 2.69, 95% CI: 1.01 to 4.37; P = 0.002), both favoring the study group. Higher years of education (β = -0.54, P < 0.001), regular physical activity (β = -0.28, P = 0.003), higher baseline Mini-Mental State Examination (MMSE) scores (β = -0.22, P = 0.001), and active hobbies (β = -0.20, P = 0.002) were significant independent predictors of CST efficacy.

DISCUSSION: Modified CST combined with medication significantly delays cognitive decline and improves QOL-AD in patients with mild-to-moderate AD. Educational attainment, lifestyle factors, and cognitive reserve are key determinants of CST efficacy. Relevant institutions should develop targeted enhancement protocols for patients with lower educational levels or insufficient cognitive reserves when implementing CST.

TRIAL REGISTRATION: Chinese Clinical Trial Registry, identifier ChiCTR2600118654, https://www.chictr.org.cn.},
}

@article {pmid42435043,
year = {2026},
author = {Dabas, A and Yadav, P and Singh, R},
title = {Exploring thiazole conjugates as cholinesterase inhibitors for Alzheimer's disease treatment.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/17568919.2026.2699679},
pmid = {42435043},
issn = {1756-8927},
abstract = {Alzheimer's Disease (AD), a major global health concern, is marked by memory loss and cognitive decline, especially in the elderly. Cholinergic hypothesis is one of the leading hypotheses toward the treatment of AD, prompting the development of cholinesterase (ChE) inhibitors. Acetylcholinesterase (AChE) remains a vital therapeutic target due to its role in enhancing acetylcholine levels and neural function. The natural products, synthetic analogs, and hybrid molecules have been evaluated as inhibitors of ChEs. Recent studies highlight thiazole-fused heterocyclic scaffolds and their derivatives as promising ChE inhibitors with neuroprotective potential. This article covers the synthesis of conjugates of thiazole with piperazine, benzimidazole, pyrazole, and other heterocyclic compounds, along with their potential as ChE inhibitors. This article will be useful to medicinal chemists and pharmaceutical industries to design and synthesize library of thiazole conjugates.},
}

@article {pmid42435703,
year = {2026},
author = {Ghose, A and Paidesetty, SK and Prusty, SK and Satapathy, BS and Panda, PK and Pakeeraiah, K and Mishra, A and Dandela, R},
title = {Rationally designed phytochemical-derived carbamate hybrids unveiling potent inhibition of cholinesterase and amyloid-β peptides.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110242},
doi = {10.1016/j.bioorg.2026.110242},
pmid = {42435703},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is most likely to be caused by the accumulation of Aβ and dysfunction of the cholinergic pathology. Oxidative damage, alterations of brain glucose metabolism, and cognitive impairment are all demonstrated in the STZ models. In order to overcome such effects, a new set of phenolic-carbamate conjugates (5a-5h) was synthesized, and their structures were elucidated using FTIR, UV, and NMR spectroscopy. The in silico studies confirmed excellent binding capabilities against AChE and Aβ targets. In vitro antioxidant assays depicted a significant free radical scavenging ability, with compound 5c exhibiting the enhanced effect. Cell line study with SH-SY5Y and PC12 cells showed greater % cell viability. AChE activity demonstrated compound 5c has significant effectiveness (IC50 = 1.98 uM). Neurobehavioral activity showed an improvement in learning and memory during behavioural assessments. In vivo antioxidant study showed greater scavenging activity (SOD, CAT, GSH), reduced of oxidative stress (MDA, NO), and the improvement in total antioxidant activity. Overall, the compound 5c has demonstrated significant results comprising decreased cholinesterase and Aβ inhibition deciphering enhanced cholinergic restoration. Hippocampal integrity was preserved, as it was confirmed by histopathological examination. It concludes that bromo-vanillyl carbamate derivative 5c (30 mg/kg) has potent antioxidant, anti-amyloid, and neuroprotective characteristics, rendering it a promising multitarget lead that warrants further investigation for the treatment of AD.},
}

@article {pmid42436821,
year = {2026},
author = {Shan, G and Zhang, Y and Ding, AA},
title = {Statistical inference for saved time based on disease progression curves in Alzheimer's disease research.},
journal = {Contemporary clinical trials communications},
volume = {52},
number = {},
pages = {101664},
pmid = {42436821},
issn = {2451-8654},
abstract = {Saved time is an easy interpretation metric that provides information to patients on how long a new treatment can delay the disease progression in time as compared to the placebo. The frequently used projection approach for saved time estimation utilizes limited information from the available data. To address that limitation, the area above the disease progression curve was proposed to estimate saved time by using more information from data. However, it is a challenge to derive the closed-form statistical inference (e.g., confidence interval of saved time) as area above the curve is quadratic relative to visit time and saved time based on the curves is nonlinearly related to the area above the curve. In this article, we derived the closed-form variance of saved time based on the area above curve approach by using Taylor expansion. We then compared the performance of the closed-form method and the existing simulation-based method to construct the confidence interval for saved time based on the area above curve approach with regard to coverage probability and interval width under various scenarios. The simulation results indicate that the proposed closed-form method has similar performance as compared to the existing method, while the closed-form method can be computationally easy in practice without additional simulations in the existing method. Data from the completed phase 2 donanemab trial were used to illustrate the application of the proposed method.},
}

@article {pmid42437499,
year = {2026},
author = {Brown, CA and Robinson, JL and Das, SR and McGrew, E and Suh, E and Van Deerlin, VM and Irwin, DJ and Nasrallah, IM and Mechanic-Hamilton, D and Yushkevich, PA and Wolk, DA and Lee, EB},
title = {Clinicopathologic Evaluation of Amyloid Clearance in Alzheimer Disease.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.13058},
pmid = {42437499},
issn = {1538-3598},
abstract = {IMPORTANCE: The long-term efficacy of amyloid-targeting therapies hinges on their ability to slow downstream neuropathologic change, but little is known about the influence of amyloid clearance on tau pathology and neurodegeneration.

OBJECTIVE: To determine the postmortem and in vivo association between amyloid levels and downstream neuropathology after treatment with aducanumab in a patient with patchy areas showing minimal residual amyloid levels.

This clinicopathologic case report from a single academic memory center includes a male carrier of the p.R47H TREM2 variant, which is associated with a higher risk of Alzheimer disease, who was in his 50s, had mild cognitive impairment, and received aducanumab while participating in a randomized clinical trial. Fourteen untreated controls, who were matched by age or presence of the TREM2 variant, also are included.

EXPOSURES: The male carrier of the p.R47H TREM2 variant had received 30 doses of aducanumab (cumulative dose of 280 mg/kg) over 4.5 years.

MAIN OUTCOMES AND MEASURES: Neuropathologic evaluation at autopsy, positron emission tomography to measure standardized uptake value ratio as a measure of amyloid and tau levels, and magnetic resonance imaging to determine longitudinal change in cortical thickness.

RESULTS: Four years after receiving the final dose of aducanumab, the patient died. An autopsy showed variable levels of amyloid pathology, including brain regions with very low levels of amyloid juxtaposed with brain regions that had typically high levels of amyloid in the deep cortical layers and only low levels of amyloid in the superficial cortical layers. Compared with the brain regions of the untreated controls, the brain regions of the patient after treatment with aducanumab showed low levels of amyloid that were preferentially found in the gyral crests, were associated with less tau pathology at autopsy, and were associated with slower longitudinal atrophy on in vivo magnetic resonance imaging (β = -0.50 [95% CI, -0.62 to -0.37]; t = -7.96 and P < .001). In contrast, the patient's brain regions with high amyloid burden were preferentially found in the sulcal depths and had similar levels of tau pathology as seen at autopsy in the untreated controls.

CONCLUSIONS AND RELEVANCE: In this case report, areas of extensive amyloid clearance after amyloid-targeting therapy were associated with less downstream neuropathologic change. In addition, amyloid clearance appears to preferentially occur in the gyral crests. Future studies should evaluate the differential mechanisms involved in amyloid clearance from superficial and deep cortical layers and in gyri and sulci because extensive amyloid clearance may be necessary to achieve downstream neuropathologic benefit after removal of amyloid.},
}

@article {pmid42438228,
year = {2026},
author = {Oh, JM and Jeong, WK and Son, HJ and Kim, SY and Oh, TW and Ji, M and Nam, JW and Baek, M and Park, JH and Shin, WH and Kim, HJ and Choi, B and Paik, MJ and Kim, H},
title = {Ameliorative Effects of a Naphthoquinone Derivative With β-Amyloid Aggregation Inhibitory Activity on Cognitive Impairment and Metabolite Analysis of the Blood and Brains of Mice.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70345},
doi = {10.1002/ddr.70345},
pmid = {42438228},
issn = {1098-2299},
support = {RS-2024-00347522//National Research Foundation of Korea (NRF)/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Mice ; Brain/metabolism/drug effects ; Male ; *Naphthoquinones/pharmacology/chemistry/therapeutic use ; Humans ; *Cognitive Dysfunction/drug therapy/metabolism ; Peptide Fragments/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Scopolamine ; Madin Darby Canine Kidney Cells ; *Neuroprotective Agents/pharmacology ; Cognitive Enhancement ; },
abstract = {Accumulation of amyloid-β (Aβ) plaques is an important cause of Alzheimer's disease (AD) pathogenesis. In this study, we evaluated Aβ aggregation inhibitory activity of synthesized naphthoquinone derivatives as well as improvement in cognitive functions and metabolite profiling of brain tissues using scopolamine (SCO)-induced mice. Compound 888 (2-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)naphthalene-1,4-dione, [TPN]) showed the highest Aβ aggregation inhibitory activity (IC50 = 0.14 μM), and was more potent than the reference compound curcumin (IC50 = 1.63 μM). Compound TPN showed effective monoamine oxidase (MAO)-A, MAO-B, acetylcholinesterase, and butyrylcholinesterase inhibitions at 10 μM, likely as candidates for multitarget-directed ligands. TPN was permeable through the blood-brain barrier, and non-toxic to MDCK and SH-SY5Y cells. TPN displayed prolonged and stable interactions with Aβ42 during molecular dynamics simulations, in contrast to the short-lived contacts observed for curcumin. Cognitive impairment was significantly improved by TPN-treatment in behavioral tests. TPN treatment attenuated Aβ-related protein expression, inflammatory responses, oxidative stress-related changes, and apoptosis-related alterations, while preserving hippocampal pyramidal neurons and their typical morphology. In metabolite profiling, TPN modulated a narrower set of pathways mainly related to amino acid and kynurenine metabolism, whereas donepezil induced broader adjustments involving amino acid, mitochondrial/energy, and lipid-related pathways compared to those in the serum and cortex of the SCO group, in contrast to those in the hippocampus. Collectively, a potent Aβ aggregation inhibitor TPN showed significant cognitive improvement, accompanying by neuroprotective effects, decreasing inflammation, and retaining neuron structures, exhibiting changed metabolic profiles compared to the control treatments. These findings suggest that TPN has cognitive-protective and neuroprotective potential under scopolamine-induced impairment conditions and warrants further validation in AD-relevant models.},
}

Animals
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
Mice
Brain/metabolism/drug effects
Male
*Naphthoquinones/pharmacology/chemistry/therapeutic use
Humans
*Cognitive Dysfunction/drug therapy/metabolism
Peptide Fragments/metabolism
Alzheimer Disease/drug therapy/metabolism
Scopolamine
Madin Darby Canine Kidney Cells
*Neuroprotective Agents/pharmacology
Cognitive Enhancement

@article {pmid42438861,
year = {2026},
author = {Liu, X and Lin, T and Jiang, Y and Luo, S and Chen, S and Chai, Y and Yang, Z and Wei, Y and Wang, H and Li, X and Xiang, YT and Sha, F and Tang, J},
title = {Antidepressant use and dementia, cognitive measures, and neuroimaging outcomes: A population-based cohort study.},
journal = {Psychological medicine},
volume = {56},
number = {},
pages = {e225},
doi = {10.1017/S0033291726104942},
pmid = {42438861},
issn = {1469-8978},
support = {82404371//National Natural Science Foundation of China/ ; 72304267//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Antidepressive Agents/therapeutic use/adverse effects ; Female ; Male ; *Dementia/epidemiology/diagnostic imaging ; Aged ; Neuroimaging ; Prospective Studies ; *Cognition/drug effects ; United Kingdom/epidemiology ; Middle Aged ; Magnetic Resonance Imaging ; Brain/diagnostic imaging ; Cohort Studies ; UK Biobank ; },
abstract = {BACKGROUND: Prior observational studies have reported conflicting results regarding whether antidepressant treatment reduces long-term dementia risk, likely due to confounding by indication and reverse causation. We aimed to investigate the association between baseline antidepressant use and incident dementia, incorporating cognitive and neuroimaging outcomes.

METHODS: We conducted a prospective cohort study using UK Biobank participants free of dementia at baseline. Antidepressant use was self-reported at baseline (2006-2010). Incident dementia was identified through linked electronic health records until December 19, 2022. Cox proportional hazards models estimated hazard ratios (HRs) for all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD), adjusting for sociodemographic, lifestyle, health-related, antidepressant indication factors, and co-medication of other anticholinergics. In subsamples, cognitive performance (n = 57,330) and structural brain imaging (n = 42,276) were examined as intermediate outcomes.

RESULTS: Among 461,464 participants, 33,721 (7.3%) reported baseline antidepressant use. Over a mean follow-up of 13.4 years, 7,922 (1.7%) developed incident dementia. Baseline antidepressant use was associated with higher risks of all-cause dementia (adjusted HR: 1.47, 95% CI 1.36-1.60), AD (1.53, 1.36-1.73), and VD (1.44, 1.23-1.70). Users performed worse on fluid intelligence and prospective memory tasks and showed lower total and gray matter volume, regional reductions in the hippocampal gray matter and basal nucleus, and greater white matter hyperintensity volume.

CONCLUSIONS: Baseline antidepressant use was linked to a higher risk of dementia, poorer cognitive performance, and adverse brain structural changes. These findings underscore the importance of judicious prescribing, regular cognitive monitoring, and consideration of non-pharmacological approaches in clinical care.},
}

Humans
*Antidepressive Agents/therapeutic use/adverse effects
Female
Male
*Dementia/epidemiology/diagnostic imaging
Aged
Neuroimaging
Prospective Studies
*Cognition/drug effects
United Kingdom/epidemiology
Middle Aged
Magnetic Resonance Imaging
Brain/diagnostic imaging
Cohort Studies
UK Biobank

@article {pmid42439335,
year = {2026},
author = {Singh, S and Singh, S and Khandelwal, V and Bharti, U and Singh, PK},
title = {Gut Microbiota in Neuroinflammation, Neurodegenerative Disorders, and Neuropsychiatric Disorders: A Comprehensive Narrative Review.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273455874260702045636},
pmid = {42439335},
issn = {1996-3181},
abstract = {Neurodegenerative and neuropsychiatric illnesses are characterized by neuroinflammation, which is driven by microglial activation, cytokine production, and breakdown of the blood-brain barrier (BBB). It is currently known that the gut microbiota plays an important role in modulating neuroimmune signaling, which in turn may trigger anxiety-like behaviors and depressive phenotypes through the microbiota-gut-brain axis. This review aims to integrate the most recent mechanistic knowledge on treatment strategies targeting the gut microbiota to modulate neuroinflammation. This review article discusses preclinical and clinical studies that investigated microbial composition, metabolite profiles, and host-microbe interactions involved in neuroinflammatory processes. However, special attention was given to signaling via the vagus nerves and bile acids, as well as to tryptophankynurenine metabolism and short-chain fatty acids (SCFAs). To examine the potential connection between the two, researchers used animal models such as germ-free animals and antibiotic-injected mice for fecal microbiota transplantation (FMT). This article defines dysbiosis as amplifying neuroinflammatory responses by altering microglial phenotypes, disrupting the blood-brain barrier, and triggering the production of pro-inflammatory cytokines. In contrast, microbiome diversity rehabilitation through the use of probiotics, prebiotics, synbiotics, and dietary modifications reduces neuroinflammatory markers and enhances cognitive and behavioral status. Clinical trials have shown considerable promise in diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), autism spectrum disorder (ASD), and depression. However, variability in treatment protocols, treatment resistance, and host-specific factors continue to pose significant challenges. This narrative review integrates mechanistic insights into microglial activation, cytokine signaling, blood-brain barrier regulation, vagal pathways, tryptophan metabolism, and short-chain fatty acids with emerging clinical evidence and therapeutic strategies, including probiotics, prebiotics, dietary modulation, and personalized microbiome-based interventions. Despite promising therapeutic potential, microbiome engineering faces important challenges, including safety concerns, lack of standardized intervention protocols, and substantial inter-individual variability in host-microbiome responses, which currently limit clinical translation. This review focuses on both neurodegenerative and neuropsychiatric disorders, examining shared neuroinflammatory mechanisms mediated by the gut-brain axis and evaluating microbiotatargeted therapeutic strategies across these disease categories. The review discusses both preventive strategies, including dietary modulation, prebiotics, and lifestyle-based microbiome interventions, as well as therapeutic approaches such as microbiota-targeted treatments aimed at mitigating neuroinflammation and disease progression.},
}

@article {pmid42439669,
year = {2026},
author = {Robert, J},
title = {What Are the Potential Therapeutic Benefits of Targeting Blood-Borne Lipoproteins in the Treatment of Alzheimer's Disease?.},
journal = {Cells},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/cells15131191},
pmid = {42439669},
issn = {2073-4409},
mesh = {Humans ; *Alzheimer Disease/drug therapy/blood/therapy ; *Lipoproteins/blood/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; Lipoproteins, HDL ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, the deposition of amyloid-β (Aβ) plaques, the formation of neurofibrillary tangles, and cerebrovascular dysfunction. Evidence suggests that blood-borne lipoproteins play a role in the disease's pathophysiology by influencing the cerebrovasculature and amyloid metabolism. Low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) can contribute to oxidative stress, endothelial dysfunction, vascular dysfunction, and the accumulation of amyloidogenic peptides, thereby exacerbating neurodegeneration. The role of lipoprotein(a) (Lp(a)) remains unclear, whereas high-density lipoprotein (HDL) is recognized for its cerebroprotective properties, including anti-inflammatory and vasoreactive functions. These properties help to maintain neuronal homeostasis and facilitate the clearance of Aβ from the brain. This review summarizes the current evidence regarding the role of lipoproteins in AD and discusses how therapeutic strategies targeting lipoprotein pathways, such as lipid-lowering agents and HDL mimetics developed for cardiovascular diseases, may benefit patients with AD.},
}

Humans
*Alzheimer Disease/drug therapy/blood/therapy
*Lipoproteins/blood/metabolism
Animals
Amyloid beta-Peptides/metabolism
Lipoproteins, HDL

@article {pmid42440180,
year = {2026},
author = {Mohamadpour, M and Amandadi, M and Javan, M and Hosseinkhani, S},
title = {A Combination of Artemisinin, N-acetylcysteine, Resveratrol, and Hesperidin Ameliorates Hippocampal Damage and Pathological Features in an Experimental Model of Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42440180},
issn = {1573-6903},
mesh = {Animals ; *Resveratrol/therapeutic use/administration & dosage ; *Alzheimer Disease/drug therapy/pathology/chemically induced/metabolism ; *Hippocampus/drug effects/pathology/metabolism ; *Hesperidin/therapeutic use/administration & dosage ; *Acetylcysteine/therapeutic use/administration & dosage ; Male ; *Artemisinins/therapeutic use/administration & dosage ; *Neuroprotective Agents/therapeutic use/administration & dosage ; Rats ; Disease Models, Animal ; Drug Therapy, Combination ; Streptozocin ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Maze Learning/drug effects ; Rats, Sprague-Dawley ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment and pathological accumulation of amyloid-β and tau proteins. This study investigated the potential neuroprotective effects of a combined treatment consisting of artemisinin, N-acetylcysteine, resveratrol, and hesperidin in a streptozotocin (STZ)-induced intracerebroventricular (ICV) rat model of AD. Twenty 8-week-old rats were divided into four groups: control, SHAM, STZ-ICV, and STZ-ICV receiving oral administration of the compound combination for 30 days. Cognitive performance was evaluated using the Morris water maze and passive avoidance tests. Neurodegenerative and molecular changes were assessed through Western blot analysis of phosphorylated tau, amyloid-β-related markers, and apoptosis- and inflammation-associated proteins. Histological analyses included Nissl staining and immunofluorescence for amyloid deposition and caspase-3 expression. Results demonstrated that STZ-ICV administration induced significant cognitive impairment, neuronal loss, and increased amyloid-β and phosphorylated tau levels. Treatment with the combined compounds partially improved behavioral performance and was associated with reductions in amyloid-β deposition, tau phosphorylation, and caspase-3 expression, along with improved neuronal preservation in the hippocampus. These findings suggest that the combined administration of artemisinin, N-acetylcysteine, resveratrol, and hesperidin exerts multi-target neuroprotective effects in an experimental AD model, potentially through modulation of oxidative stress, neuroinflammation, and apoptotic pathways. However, further studies are required to evaluate pharmacokinetics, safety, and translational relevance before clinical application.},
}

Animals
*Resveratrol/therapeutic use/administration & dosage
*Alzheimer Disease/drug therapy/pathology/chemically induced/metabolism
*Hippocampus/drug effects/pathology/metabolism
*Hesperidin/therapeutic use/administration & dosage
*Acetylcysteine/therapeutic use/administration & dosage
Male
*Artemisinins/therapeutic use/administration & dosage
*Neuroprotective Agents/therapeutic use/administration & dosage
Rats
Disease Models, Animal
Drug Therapy, Combination
Streptozocin
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Maze Learning/drug effects
Rats, Sprague-Dawley

@article {pmid42440193,
year = {2026},
author = {Adiniaev, Y and Omar, M and Daniel, O and Timor, TM and Barash, Y and Brook, OR and Klang, E and Gorenshtein, A},
title = {Generative large language models in the clinical management of Alzheimer's disease and mild cognitive impairment.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42440193},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/therapy/diagnosis ; *Cognitive Dysfunction/therapy/diagnosis ; *Large Language Models ; Generative Artificial Intelligence ; },
abstract = {BACKGROUND: Dementia affects over 55 million people worldwide. Mild cognitive impairment (MCI) often precedes Alzheimer's disease (AD). Clinical management requires integrating uncertain evidence from neuropsychological testing, neuroimaging, and biomarkers. Large language models (LLMs) also generate probabilistic outputs, but whether they can reliably support diagnostic, therapeutic, or educational tasks in AD and MCI has not been systematically examined.

METHODS: We searched PubMed, Scopus, and PubMed Central (January 2023 to April 2026) for studies evaluating generative LLMs on clinical tasks in Alzheimer's disease (AD) or mild cognitive impairment (MCI). Risk of bias was assessed using QUADAS-AI and AXIS. Narrative synthesis followed the SWiM guideline.

PROSPERO: CRD420261372436.

RESULTS: Eleven studies were included: diagnosis (n = 3), treatment guidance (n = 2), and patient/caregiver education (n = 8); two studies contributed to multiple domains. Diagnostic models achieved high internal accuracy (0.94-0.97) but declined on external validation; three-way classification accuracy dropped approximately 7% points, and MMSE-prediction R² collapsed from 0.90 to 0.25 on an external dataset. Treatment guidance approached but did not match structured clinical guidelines. Educational outputs were rated moderate to high quality but lacked source attribution and exceeded recommended reading levels; retrieval augmentation improved usability without improving accuracy. Hallucination was quantified in only 2 of 11 studies, and no study evaluated prospective clinical use.

CONCLUSIONS: Current evidence does not support the use of LLMs for diagnosis, treatment selection, or patient education in AD/MCI without clinician oversight. These findings reflect the specific model versions, prompting strategies, and evaluation conditions in place at the time of each study, and are further limited by small heterogeneous evaluations, sparse hallucination measurement, and absence of prospective clinical validation.},
}

Humans
*Alzheimer Disease/therapy/diagnosis
*Cognitive Dysfunction/therapy/diagnosis
*Large Language Models
Generative Artificial Intelligence

@article {pmid42440589,
year = {2026},
author = {Huang, X and Xu, G and Zhou, Y and Wang, D and Ai, L and Liu, H and Fan, A and Wang, L and Zhang, P},
title = {P2-engineered exosomes encapsulating curcumin alleviate cognitive decline in AD-like mice by improving microglia-related neuropathology.},
journal = {Materials today. Bio},
volume = {39},
number = {},
pages = {103388},
doi = {10.1016/j.mtbio.2026.103388},
pmid = {42440589},
issn = {2590-0064},
abstract = {Natural exosomes, as drug carriers, can deliver anti-inflammatory agents across the blood-brain barrier (BBB) to lesion sites in the brain, thereby demonstrating immense potential in the treatment of brain inflammation-related diseases. However, the application of natural exosomes is constrained by their poor targeting ability. Herein, we report a novel drug delivery system (P2-Exo-Cur) constructed by engineering exosomes to display the P2 peptide on their surface, thereby enabling targeted delivery of curcumin to microglia. Our results revealed that P2-Exo-Cur possesses a nanoscale membrane structure and can efficiently deliver curcumin to microglia both in vitro and in vivo. This technology provides a microglia-targeted delivery approach for anti-inflammatory agents such as curcumin, while overcoming the undesirable off-target effects that limit their efficacy. Furthermore, treatment of lipopolysaccharide (LPS)-induced inflammatory BV2 cell models with P2-Exo-Cur significantly suppressed the polarization of BV2 cells toward the M1 phenotype, as well as the secretion of pro-inflammatory cytokines. Finally, we also validated the excellent therapeutic potential of this technology in the 5xFAD mouse model. In conclusion, in this study, we for the first time constructed engineered exosomes that can specifically bind to the NCAM protein on microglia to achieve precise delivery of curcumin by expressing the P2 peptide on their surface, exerting beneficial effects in AD treatment without causing significant adverse effects. This strategy may offer a non-invasive and innovative therapeutic method for the management of brain inflammation-related diseases.},
}

@article {pmid42440665,
year = {2026},
author = {Han, J and Sun, Y and Song, Y and Wu, Y and Wang, X},
title = {The latest research progress of ligustilide in the prevention and treatment of central nervous system disorders.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1843537},
doi = {10.3389/fphar.2026.1843537},
pmid = {42440665},
issn = {1663-9812},
abstract = {BACKGROUND: Ligustilide (LIG), a natural phthalide compound mainly isolated from Angelica sinensis and Ligusticum chuanxiong, has attracted increasing attention because of its diverse pharmacological activities, including anti-inflammatory, antioxidant, anti-apoptotic, and neuroprotective effects. Emerging studies suggest that LIG may have therapeutic relevance in central nervous system (CNS) disorders.

PURPOSE: This review systematically summarizes the pharmacological effects, molecular mechanisms, pharmacokinetic characteristics, metabolism, safety profile, and therapeutic potential of LIG in CNS disorders.

METHODS: Relevant studies published up to 26 October 2025 were retrieved from PubMed, Web of Science, and Scopus using keywords related to ligustilide, central nervous system disorders, pharmacokinetics, metabolism, and toxicity. After removing duplicate records and excluding reviews, editorials, and irrelevant articles, 55 eligible original studies were included in this review.

RESULTS: Current evidence indicates that LIG exerts neuroprotective effects in multiple CNS disorders, including ischemic stroke, cerebral ischemia-reperfusion injury, vascular dementia, Alzheimer's disease, Parkinson's disease, traumatic brain injury, and anxiety disorders. Its mechanisms mainly involve modulation of PI3K/Akt, MAPK, NF-κB, Nrf2/ARE, AMPK, and other signaling pathways, leading to reduced oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction. In addition, available studies suggest that LIG can cross the blood-brain barrier and shows relatively favorable safety in preclinical models.

CONCLUSION: LIG demonstrates broad neuroprotective potential in preclinical studies and may represent a promising candidate for CNS disease intervention. However, its poor chemical stability, low oral bioavailability, limited toxicity evaluation, and lack of clinical evidence remain major challenges for translational application. Further studies are required to optimize delivery strategies and validate its efficacy and safety in clinical settings.},
}

@article {pmid42427890,
year = {2026},
author = {Lin, F and Teng, Y},
title = {Magnolol mitigates neuroinflammation via NF-κB/IL-6/IL-1β pathways in AlCl3-induced Alzheimer's disease: insights from in-vivo and in-silico investigations.},
journal = {3 Biotech},
volume = {16},
number = {8},
pages = {314},
pmid = {42427890},
issn = {2190-572X},
abstract = {The neuroprotective effectiveness of natural substances against neuroinflammatory pathways linked to Alzheimer's disease (AD) is still not well understood. In this study, we used both in vivo and in silico methods to assess the therapeutic potential of magnolol at dosages of 25 and 50 mg/kg body weight in a rat model of AD produced by aluminium chloride (AlCl3). Significant cognitive impairments, elevated levels of malondialdehyde (MDA), and increased expression of important neuroinflammatory mediators, including nuclear factor kappa-B (NF-κB), interleukin (IL-6), and interleukin-1β (IL-1β), were all brought on by exposure to AlCl3. Magnolol treatment markedly reduced the levels of pro-inflammatory cytokines, lactate dehydrogenase (LDH), and nitric oxide (NO), improved cognitive function, and strengthened antioxidant defence systems as shown by increased glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) activities. Histopathological examination further validated Magnolol's neuroprotective properties, showing decreased neuronal degeneration. Magnolol has substantial binding affinities for NF-κB, IL-6, and IL-1β, according to molecular docking and dynamic modelling studies, indicating that it can directly influence neuroinflammatory signalling pathways. Overall, these results show that magnolol has important neuroprotective effects by reducing oxidative stress and inhibiting important inflammatory mediators, underscoring its potential as an effective treatment option for AD.},
}

@article {pmid42428551,
year = {2026},
author = {Li, W and Yu, X and Guo, C and Huang, Y and Wei, Z and Liu, Y and Wang, JZ and Liu, R and Ji, W and Duan, Q and Wang, J and Wang, G and Wang, X},
title = {Acylglycerol Kinase Inhibition Restores Mitophagy and Alleviates Alzheimer's Disease Pathology.},
journal = {MedComm},
volume = {7},
number = {7},
pages = {e70863},
pmid = {42428551},
issn = {2688-2663},
abstract = {Mitophagy is a conserved cellular process that removes dysfunctional or excess mitochondria. Increasing evidence suggests that impaired mitophagy plays a crucial role in AD development. Promoting mitophagy has been shown to be protective in models of AD, representing an important target of Alzheimer's disease (AD). However, the molecular mechanisms underlying impaired mitophagy in AD are still elusive. Here, we provide evidence that highly expressed acylglycerol kinase (AGK), a mitochondrial lipid kinase associated with mitochondrial protein transport, glycolysis, and platelet formation, is a key mediator of mitophagy in AD. We found that AGK promoted the binding of ATPase family AAA domain containing 3A to translocase of the inner mitochondrial membrane 23 and sequentially increased mitochondrial import of PTEN-induced putative kinase 1, leading to the decrease of mitophagy. Further investigations revealed that the AGK downregulation in neuronal cells and APP/PS1 mice enhanced mitophagy, increased mitochondrial membrane potential, decreased pathological Tau/Aβ and neuroinflammation, and alleviated cognitive dysfunctions in the mice. Altogether our findings indicate that AGK plays a critical role in mediating mitophagy defects in AD; furthermore, downregulation of AGK promotes mitophagy and the decrease of Aβ and pathological Tau, providing an encouraging therapeutic treatment for AD.},
}

@article {pmid42426112,
year = {2026},
author = {Kim, Y and Choudhary, A and Kim, H and Teale, P and McConnell, B and Al Borno, M},
title = {Comparing vibrotactile stimulation to combined visual and auditory stimulation for 40 Hz gamma entrainment.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-60911-1},
pmid = {42426112},
issn = {2045-2322},
abstract = {There is significant interest in combined visual and auditory stimulation to entrain 40 Hz gamma oscillations for the treatment of Alzheimer's disease and other neurological conditions such as stroke and insomnia. In this work, we compared another sensory modality-vibrotactile stimulation delivered with a glove-to visual and auditory stimulation in 15 healthy participants in terms of electroencephalogram (EEG) responses and subjective experience. We found that vibrotactile stimulation from the glove could evoke 40 Hz EEG responses in the central, frontal and, to a lesser extent, occipital cortices. We also observed distinct patterns of functional connectivity between the two stimulation modalities. Participants preferred the vibrotactile stimulation over the visual and auditory stimulation. Our study supports future investigations on vibrotactile stimulation for the treatment of neurological conditions.},
}

@article {pmid42426158,
year = {2026},
author = {Vöglein, J and Levin, J and Stögmann, E and Haass, C and Höglinger, GU and Frölich, L and Jessen, F},
title = {Attitudes of specialist memory-clinic patients with early symptomatic Alzheimer's disease towards lecanemab: results from a multicenter survey in Europe.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42426158},
issn = {2045-2322},
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology/genetics ; Female ; Male ; Aged ; Europe ; Surveys and Questionnaires ; Cross-Sectional Studies ; Middle Aged ; Aged, 80 and over ; Memory ; },
abstract = {Lecanemab approval in the European Union (EU) was granted after a delay. This delay resulted in concerns from many stakeholders, but attitudes of patients with early symptomatic Alzheimer's disease receiving specialist memory-clinic care remained insufficiently assessed. Therefore, we evaluated attitudes of specialist memory-clinic patients with early symptomatic Alzheimer's disease towards lecanemab in Europe. In this anonymous, international, multicentre, cross-sectional survey conducted from October 14, 2024 to February 18, 2025, a standardized, expert-developed questionnaire assessed attitudes towards lecanemab treatment and EU approval. Before answering four binary questions, participants received brief explanatory information on expected clinical benefit, amyloid-related imaging abnormalities (ARIA), and the increased ARIA risk associated with APOE ε4 homozygosity. The survey was conducted in specialist memory clinics within the European Alzheimer's Disease Consortium (EADC), the German memory clinic network (DNG), and Austrian memory centers. Available recruitment-flow data were limited to completed questionnaires because the survey was anonymous and distributed locally. 281 patients with early symptomatic Alzheimer's disease completed the survey. Network-level sample sizes were EADC n = 202, DNG n = 60, and Austria n = 19; country-specific sample sizes within the EADC and response rates were not available. Endorsement was high for both individual treatment with lecanemab (81.9%, 95% confidence interval [CI] 76.8-86.2) and general EU approval (91.8%, 95% CI 87.9-94.7). Endorsement remained substantial, but was lower, in the context of APOE ε4 homozygosity (treatment: 61.2%, 95% CI 55.2-66.9; approval: 76.5%, 95% CI 71.1-81.3). Approval-related questions received higher endorsement than treatment-related questions (84% vs. 72%; p < 0.001). Support for approval for APOE ε4 homozygotes declined after regulatory recommendations excluded this group (from 87% to 73%; p = 0.025); this comparison reflects independent respondents completing the anonymous survey before versus after November 14, 2024. Network-level comparisons were descriptive and underpowered for geographic inference. High endorsement within this specialist memory-clinic sample suggests perceived value of access to lecanemab. Greater endorsement for approval than for individual treatment may reflect support for treatment access beyond personal treatment choice, but alternative explanations such as social desirability, acquiescence, misunderstanding, or effects of the survey information cannot be excluded. The findings should not be generalized beyond specialist memory-clinic patients and should be interpreted in view of potential selection and response biases, absent response-rate data, and the brief, non-validated binary questionnaire.},
}

Humans
*Alzheimer Disease/drug therapy/psychology/genetics
Female
Male
Aged
Europe
Surveys and Questionnaires
Cross-Sectional Studies
Middle Aged
Aged, 80 and over
Memory

@article {pmid42426326,
year = {2026},
author = {Wu, Q and Fan, D and Ren, J and Xing, Y and Chen, Z and Jin, H and Lu, Y and Wang, X and Zheng, H},
title = {SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42426326},
issn = {1559-1182},
mesh = {*Sumoylation/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; Humans ; *Mitochondria/metabolism/pathology ; Animals ; Mitophagy ; },
abstract = {Mitochondria, as the primary energy-generating organelles in neurons, play a pivotal role in regulating cellular metabolism. Given the post-mitotic nature and long lifespan of neurons, they are particularly vulnerable to the cumulative burden of mitochondrial damage. In response to various physiological and stress signals, a sophisticated mitochondrial quality control (MQC) system has evolved, which encompasses mitochondrial biogenesis, dynamics (fission and fusion), and mitophagy. This coordinated network acts as a critical surveillance mechanism to eliminate damaged components and maintain a healthy mitochondrial pool. The small ubiquitin-like modifier (SUMO) pathway, involving reversible SUMOylation and deSUMOylation, has emerged as a key regulator of MQC by directly modifying its core components. Dysregulation of the SUMO pathway disrupts mitochondrial homeostasis, and the resulting mitochondrial dysfunction is increasingly recognized as a central pathogenic mechanism in neurodegenerative diseases. This review systematically examines the role of the SUMO pathway in regulating MQC and its implications in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntington's disease. Finally, we discuss the therapeutic potential and translational challenges of targeting the SUMO pathway for the treatment of neurodegenerative diseases.},
}

*Sumoylation/physiology
*Neurodegenerative Diseases/metabolism/pathology
Humans
*Mitochondria/metabolism/pathology
Animals
Mitophagy

@article {pmid42427159,
year = {2026},
author = {Bevins, EA and Léger, GC and Herman, MA and Ringman, JM and Roy, S and Shtrahman, M and Pa, J and Feldman, HH},
title = {Safety considerations of gene-based therapies for Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71515},
pmid = {42427159},
issn = {1552-5279},
support = {//Epstein Family Alzheimer's Research Collaboration (EFARC)/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/genetics ; *Genetic Therapy/adverse effects/methods ; Gene Therapy Agents ; Animals ; Dependovirus/genetics ; Oligonucleotides, Antisense/therapeutic use ; },
abstract = {Gene-based therapies show increasing promise for the treatment of neurologic disease. In 2016, nusinersen, an RNA-based therapy, was approved for children with spinal muscular atrophy (SMA). Over 200 clinical trials have utilized gene therapy approaches for a host of neurodegenerative and neuromuscular disorders, including Alzheimer's disease (AD).[1] Delivering gene-based therapies to the central nervous system (CNS) has raised safety concerns. As clinical trials utilizing gene therapy paradigms are undertaken and as approved therapies translate into clinics, a better understanding of safety issues and monitoring parameters is needed. We describe current therapeutic approaches for AD using gene-based therapies such as adeno-associated virus gene therapy and RNA interference by antisense oligonucleotides (ASOs) and undertake a review of medical safety considerations for existing AD gene therapy trials. We identify challenges in analyzing medical safety data currently available and provide guidelines for making this information more accessible and interpretable for the future.},
}

Humans
*Alzheimer Disease/therapy/genetics
*Genetic Therapy/adverse effects/methods
Gene Therapy Agents
Animals
Dependovirus/genetics
Oligonucleotides, Antisense/therapeutic use

@article {pmid42427416,
year = {2026},
author = {Cvek, B},
title = {Comment on "Disulfiram as an anti-inflammatory agent: mechanisms, nano-delivery strategies, and applications in non-oncologic diseases" by Q. Jiang, M. Jiang, Y. Lv, X. Zhang, S. Wang and J. Zhao, RSC Adv., 2025, 15, 36344.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42427416},
issn = {2046-2069},
abstract = {The referenced article reviews the purported anti-inflammatory properties of disulfiram, an anti-alcohol drug also known as Antabuse. However, the anti-inflammatory properties of disulfiram should be considered alongside a wealth of scientific research demonstrating its potential to treat various conditions, including cancers, Alzheimer's disease, sepsis, tuberculosis, blindness and heart conditions. I argue that almost all these results are unreliable using basic chemical knowledge. Most importantly, disulfiram has never been shown to be an active molecule in vivo. The authors of the referenced article did not address this fact at all. Testing disulfiram in vitro yields misleading and dangerous pseudoscientific "results", suggesting that it could be a potential treatment for an ever-growing list of diseases.},
}

@article {pmid42427668,
year = {2026},
author = {Pallerla, AV and Lucido, CC and Saito, K and Nolt, GL and Arbones-Mainar, JM and Funnell, JL and Satish, D and Smith, LM and Stephens, IO and Goulding, D and MacLean, SM and Olmsted, SM and Adreon, D and Hernandez, G and Golden, LR and Persohn, S and Macauley, SL and Territo, PR and Morganti, J and Johnson, LA},
title = {Anti-amyloid immunotherapy drives APOE4 specific increases in glial reactivity, perivascular immune activation, and ARIA-like events.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.26.734793},
pmid = {42427668},
issn = {2692-8205},
abstract = {Anti-amyloid antibodies represent the first disease modifying therapeutics for Alzheimers disease (AD). Adoption of these novel treatments has been slowed by the occurrence of amyloid related imaging abnormalities (ARIA) - treatment-associated edema (ARIA-E) or microhemorrhages (ARIA-H) that disproportionately affect carriers of the E4 allele of apolipoprotein E (APOE). With E4 carriers comprising nearly 70% of the AD population, there is a critical need to understand the unique vulnerability of E4 carriers to these events. To address this gap, we utilized the EFAD mouse model - which expresses human APOE isoforms on the 5xFAD background of amyloidosis - to directly compare the effects of anti-amyloid therapy across APOE genotypes. 9-month-old E2, E3, and E4FAD mice received weekly injections of chimeric Aducanumab (chAdu) or IgG control for 12 weeks, to assess APOE isoform-specific effects on amyloid dynamics, ARIA-H-like microhemorrhages, and underlying cellular and transcriptomic responses. E4FAD mice demonstrated plaque reductions with accompanying increases in microhemorrhages (measured on both MRI and histology), and increases in microglial and astrocyte reactivity - especially in the perivascular compartment. Additionally, vascular branching analysis and parallel single cell and spatial transcriptomics revealed a loss of vascular plasticity and increased inflammatory and immune signaling in the neurovascular units of E4FAD mice. Together, these findings suggest the cerebrovasculature of E4s is uniquely susceptible to antibody mediated vascular damage and provide immunological targets for the assessment or mitigation of ARIA risk in this highest need population.},
}

@article {pmid42422549,
year = {2026},
author = {Ruesga Mundo, S},
title = {Hierarchical-circular model of biological memory: a multilevel hypothesis for pathogenesis and allostatic integrity in Alzheimer's disease and related dementias.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1841647},
pmid = {42422549},
issn = {2813-3919},
abstract = {INTRODUCTION: Alzheimer's disease and related dementias remain largely resistant to disease-modifying therapies, despite decades of research focused on linear neuropathological pathways such as beta-amyloid and tau. Persistent paradoxes-including the dissociation between pathology burden and clinical expression, the impact of early-life stress, and the role of systemic factors-indicate the need for integrative theoretical frameworks. This article proposes a multilevel hypothesis conceptualizing dementias as disorders of biological memory and allostatic integrity rather than isolated brain pathologies.

HYPOTHESIS: The Hierarchical-Circular Model of Biological Memory posits that dementia emerges from progressive disruptions in a circular, multilevel system that encodes and stabilizes biological information across the lifespan. The model is organized around the unifying principle "Signal → Plasticity → Stable State" and integrates five interconnected levels: (1) morphogenetic programming and genetic architecture, (2) epigenetic molecular memory, (3) allostatic load and systemic physiological adaptation, (4) the Psychological-Neurological-Endocrine-Immunological (PNEI) network, and (5) interoceptive-neuronal integration. At any level, perturbation can propagate bidirectionally through the system, establishing maladaptive stable states that manifest clinically as dementia.

DEVELOPMENT OF THE HYPOTHESIS: Through a structured synthesis of longitudinal, mechanistic, and multisystem studies (2010-2025), the model specifies how gene-environment interactions, epigenetic modifications, cumulative allostatic load, neuroimmune dynamics, and altered interoceptive timescales jointly shape vulnerability and resilience. The concept of allostatic integrity is introduced as a dynamic systems-level property-distinct from allostatic load-that explains why similar neuropathological burdens may result in divergent clinical trajectories. Distinct dementia phenotypes are proposed to reflect different patterns of circular reinforcement across the five levels.

TESTABLE PREDICTIONS: This framework generates concrete, falsifiable predictions: (1) composite indices of allostatic integrity will outperform single biomarkers in predicting conversion from mild cognitive impairment to dementia; (2) multidomain interventions targeting more than one system level will have multiplicative, rather than additive, effects on slowing cognitive decline; (3) patients with similar amyloid/tau profiles but contrasting allostatic integrity will show markedly different trajectories of clinical progression; and (4) allostatic integrity moderates the protective effect of cognitive reserve, a pattern not predicted by reserve frameworks alone.

CONCLUSION: The Hierarchical-Circular Model of Biological Memory offers a unifying hypothesis for Alzheimer's disease and related dementias that bridges genetic, epigenetic, physiological, neuroimmune, and interoceptive processes across the lifespan. By reframing dementias as failures of biological memory and allostatic integrity, the model provides a conceptual roadmap for mechanistic research, multidomain prevention, and personalized treatment strategies.},
}

@article {pmid42423023,
year = {2026},
author = {Kim, S and Oda, H and Oyama, R and Makishi, R and Bade, S and Bade, S and Ally, I and Iijima, Y and Gibo, Y and Minami, K and Fukuzawa, F and Sanji, S and Inamine, K and Kishi, H and Huh, S and Tanifuji, T and Nagahiro, M and Watanabe, N},
title = {Efficacy, safety and policy implications of anti-amyloid monoclonal antibodies for Alzheimer's disease: protocol for a living systematic review and meta-analysis.},
journal = {BJPsych open},
volume = {12},
number = {4},
pages = {e182},
doi = {10.1192/bjo.2026.12044},
pmid = {42423023},
issn = {2056-4724},
abstract = {BACKGROUND: Dementia affects approximately 6-13% of adults aged 65 years and older, with Alzheimer's disease accounting for most cases. Established symptomatic therapies, including acetylcholinesterase inhibitors and memantine, provide limited benefit and do not modify disease progression. Multiple monoclonal antibodies (mABs) targeting different amyloid-β species have been developed as potential disease-modifying therapies; because some agents have entered clinical use whereas others remain investigational, a continuously updated synthesis of their efficacy and safety is needed.

AIMS: To evaluate the efficacy and safety of all anti-amyloid mABs for adults with Alzheimer's disease, using a living systematic review and meta-analysis.

METHOD: We will conduct a living systematic review and meta-analysis in accordance with the Cochrane Handbook, Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 and the PRISMA extension for living systematic reviews. Randomised controlled trials comparing any approved or investigational anti-amyloid mAB with placebo, standard care or active comparators will be included. Searches of Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform will be updated every 6 months. Meta-analyses will be conducted separately for each antibody molecule using random-effects models. Critical outcomes include global clinical change and disease severity, cognitive abilities, functional ability and dependency, and safety (serious adverse events, treatment discontinuation and amyloid-related imaging abnormalities). Important outcomes include neuropsychiatric symptoms, quality of life and health system outcomes. Certainty of evidence will be assessed using the methodology Grading of Recommendations, Assessment, Development and Evaluation.

RESULTS: This article describes a protocol; therefore, no review findings are available at this stage.

CONCLUSIONS: This living systematic review will provide an up-to-date synthesis of the benefits and harms of anti-amyloid monoclonal antibodies to inform clinical decision-making and health-system planning in Alzheimer's disease.},
}

@article {pmid42423667,
year = {2026},
author = {Huang, Q and Zuo, Y and Xie, Y and Liu, Z and Wang, L and Xu, H and Yu, M and Liu, C},
title = {A nose-to-brain drug delivery system targeting mitochondrial dysfunction: application potential and future prospects of chitosan nanogels in Alzheimer's disease.},
journal = {Biomaterials science},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6bm00624h},
pmid = {42423667},
issn = {2047-4849},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal degeneration and cognitive impairment. One of its core pathologies involves energy metabolism disruption and oxidative stress resulting from mitochondrial dysfunction. Traditional drugs struggle to effectively cross the blood-brain barrier (BBB), while the nasal-brain drug delivery system offers a novel approach for achieving direct brain access. Chitosan, a biodegradable natural polymer with strong mucosal adhesion properties, has been extensively utilized in recent years to construct nanogel carriers. This approach enhances drug retention and absorption in the nasal epithelium, enabling targeted delivery to the brain via the olfactory or trigeminal nerve pathways. This paper provides a systematic review of research progress on chitosan nanogel-based naso-cerebral drug delivery systems targeting mitochondrial dysfunction, focusing on their molecular mechanisms in improving mitochondrial energy metabolism, scavenging excess reactive oxygen species (ROS), suppressing neuroinflammation, and regulating apoptosis. Additionally, this paper analyzes the design principles of various modification strategies-such as triphenylphosphine (TPP) modification, pH/ROS responsiveness, and drug-loaded nanozyme complexes-along with their efficacy validation in AD models. It further explores the future development trends of chitosan nanogel-mediated multi-target intervention and smart-responsive nasal-brain delivery systems, offering new directions for precision treatment of AD.},
}

@article {pmid42423809,
year = {2026},
author = {Yousef, AI and El-Twab, SMA and Khadrawy, SM and Abdel-Moneim, A and Khalil, RG},
title = {Polydatin inhibits hippocampal neurodegeneration in diabetic rats via modulation of oxidative stress and NF-kB/COX-2/IL-6 inflammatory pathway.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42423809},
issn = {1573-7365},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Glucosides/pharmacology/therapeutic use ; *Stilbenes/pharmacology/therapeutic use ; *Hippocampus/drug effects/metabolism/pathology ; Male ; Rats ; Cyclooxygenase 2/metabolism ; *Diabetes Mellitus, Experimental/metabolism/drug therapy ; *NF-kappa B/metabolism ; Interleukin-6/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Molecular Docking Simulation ; *Neurodegenerative Diseases/metabolism/drug therapy ; },
abstract = {Impaired insulin function and persistent hyperglycemia damage the brain of diabetics and raise the risk of Alzheimer's disease (AD). Although polydatin (PLD) possesses promising biological effects, no major study has yet explored its anti-neurodegenerative efficacy in the hippocampus. This study therefore aims to investigate the probable protective effects of PLD against hippocampal neurodegeneration in diabetic rats, as well as explore its in-silico inhibitory activity against two key enzymes implicated in the progression of AD. Experimental diabetes was induced in male albino rats then PLD was administered orally to the diabetic rats (50 mg/kg b.wt.) daily for four weeks. In silico molecular docking was used to predict the interactions of PLD against BACE1 and AChE. PLD treatment significantly improved diabetic parameters, lowering blood glucose and raising serum insulin. Excitingly, PLD markedly alleviated oxidative stress by reducing lipid peroxidation and nitric oxide levels while enhancing antioxidant defenses (elevated GPx activity and GSH content) in the hippocampus of diabetic rats. PLD also suppressed neuroinflammation by down-regulating NF-κB, COX-2, and IL-6 mRNA expression. Furthermore, PLD significantly elevated the protein level of IDE while lowered Aβ1-42 level. In silico, PLD revealed potent binding affinity for BACE1 (-8.6 Kcal/mol) and AChE (-10.5 Kcal/mol), interacting with key residues, indicating its inhibition potential. Overall, PLD effectively reduced neurodegeneration in the hippocampus of diabetic rats via inhibiting oxidative stress, inflammation, and Aβ1-42 accumulation. PLD may act as a promising multi-target anti-neurodegenerative candidate, capable of simultaneously modulating multiple pathways and more experimental validation are needed in the future.},
}

Animals
*Oxidative Stress/drug effects
*Glucosides/pharmacology/therapeutic use
*Stilbenes/pharmacology/therapeutic use
*Hippocampus/drug effects/metabolism/pathology
Male
Rats
Cyclooxygenase 2/metabolism
*Diabetes Mellitus, Experimental/metabolism/drug therapy
*NF-kappa B/metabolism
Interleukin-6/metabolism
Neuroprotective Agents/pharmacology/therapeutic use
Signal Transduction/drug effects
Molecular Docking Simulation
*Neurodegenerative Diseases/metabolism/drug therapy

@article {pmid42424238,
year = {2026},
author = {Tshimbombu, TN and Thurmann, KE and Decourt, B and Nyalundja, AD and Shardow, SB and Amoako, ME and Iragi, GM and Mwambali, JA and Sabbagh, MN},
title = {Autophagy in Alzheimer's disease: mechanisms, clinical trials, and horizons.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-21},
doi = {10.1159/000553506},
pmid = {42424238},
issn = {1660-2862},
abstract = {BACKGROUND: Alzheimer's disease (AD) is an incurable progressive neurodegenerative disorder characterized by the pathological accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles in the brain. Recent findings have identified dysregulation of autophagy, a cellular mechanism for degradation and recycling, as a crucial contributor to the pathogenesis of AD. This narrative review examines the role of autophagy in the metabolism of Aβ and tau and evaluates current therapeutic strategies aimed at modulating autophagic pathways.

SUMMARY: Autophagy is governed by the key molecular regulators mammalian target of rapamycin, adenosine monophosphate-activated protein kinase, Beclin-1, and transcription factor EB, which collectively control the clearance of protein recycling, including aggregates, inside cells. Pharmacological agents such as rapamycin, resveratrol, and trehalose, alongside sigma-1 receptor agonists and gene therapy approaches, have demonstrated potential in modulating autophagy in preclinical and clinical studies. Despite these advances, significant challenges persist; namely, neuronal heterogeneity, optimal timing for therapeutic intervention, and the absence of reliable biomarkers to monitor autophagic activity and treatment efficacy.

KEY MESSAGES: Targeting autophagy offers a promising and potentially safe avenue for slowing AD progression. Future investigations should prioritize the development of selective autophagy modulators and personalized treatment strategies to restore autophagic flux and enhance clinical outcomes in patients with AD.},
}

@article {pmid42424917,
year = {2026},
author = {Lapmanee, S and Thonapan, N and Sriwong, S and Bhubhanil, S and Wongchitrat, P and Charoenphon, N and Ngernsutivorakul, T and Hooncharoen, K and Bunwatcharaphansakun, P and Khongkow, M and Namdee, K},
title = {RGD-functionalized cannabidiol lipid nanoparticles improve brain delivery and alleviate cognitive and metabolic dysfunction via gut-brain axis modulation in an Alzheimer's disease model.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {201},
number = {},
pages = {119724},
doi = {10.1016/j.biopha.2026.119724},
pmid = {42424917},
issn = {1950-6007},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss. Evidence links gut-brain axis dysfunction and metabolic disturbances to AD. Although cannabidiol (CBD) has neuroprotective effects, its use is limited by poor bioavailability and brain delivery.

METHODS: Arginylglycylaspartic acid (RGD)-functionalized, CBD-loaded lipid nanoparticles (CBD/LNP-RGD) were developed to enhance targeted delivery across the blood-brain barrier (BBB) via integrin αvβ3-mediated transcytosis. Cellular uptake and BBB permeability were evaluated in vitro. Anti-inflammatory and antioxidant effects were assessed in Aβ/LPS-induced models. In vivo efficacy was examined using cognitive-behavioral tests, including the novel object recognition and the Morris water maze. Metabolic parameters, histopathology, synaptic protein expression, and gut barrier integrity were also evaluated.

RESULTS: CBD/LNP-RGD demonstrated a 3-fold increase in cellular uptake and a 65% enhancement in BBB transport compared to non-targeted formulations. Treatment significantly reduced pro-inflammatory cytokines (i.e., IL-6 and TNF-α, p < 0.001) and intracellular reactive oxygen species (p < 0.001). In vivo, CBD/LNP-RGD improved cognitive performance comparable to Donepezil (p < 0.001). Additionally, it normalized glycemic control, insulin resistance, and triglyceride levels without hepatic or renal toxicity. At the tissue level, CBD/LNP-RGD reduced Aβ and tau pathology, restored short-chain fatty acids, preserved hippocampal neuronal integrity, and upregulated synaptophysin and PSD-95 proteins. Enhanced intestinal barrier function was evidenced by increased expression of tight junction proteins ZO-1 and occludin.

CONCLUSIONS: CBD/LNP-RGD represents a multifunctional nanotherapeutic platform that improves brain delivery and exerts neuroprotective, anti-inflammatory, antioxidant, and metabolic regulatory effects. Its ability to modulate both central pathology and the gut-brain axis highlights its potential as a disease-modifying strategy for Alzheimer's disease.},
}

@article {pmid42425064,
year = {2026},
author = {Rudman, MD and Ulrich, JD and Holtzman, DM},
title = {Recent advances in Alzheimer's disease: From molecular mechanisms to therapeutic strategies.},
journal = {Cell},
volume = {189},
number = {14},
pages = {4193-4224},
doi = {10.1016/j.cell.2026.06.006},
pmid = {42425064},
issn = {1097-4172},
mesh = {*Alzheimer Disease/therapy/pathology/drug therapy/metabolism/immunology ; Humans ; Animals ; Apolipoproteins E/metabolism/genetics ; Plaque, Amyloid/pathology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) remains the leading cause of dementia worldwide and an escalating global health crisis. The hallmark amyloid plaques and neurofibrillary tangles (NFT) are now known to be accompanied by a complex array of pathologies that culminate in neurodegeneration and cognitive decline. New disease-modifying therapies for AD can now slow cognitive decline through the removal of amyloid plaques from the brain, but treatments to stop or prevent cognitive impairment remain elusive. In this review, we summarize the most recent updates in AD research on pathologic disease mechanisms and therapeutic strategies, highlighting advancements in apolipoprotein E (APOE) biology, neuroimmunology, biomarker discovery, and initial experience with new disease-modifying therapies. These important discoveries are revolutionizing AD diagnosis and treatment and provide hope for a future where AD is not only treatable but also preventable.},
}

*Alzheimer Disease/therapy/pathology/drug therapy/metabolism/immunology
Humans
Animals
Apolipoproteins E/metabolism/genetics
Plaque, Amyloid/pathology
Amyloid beta-Peptides/metabolism

@article {pmid42425385,
year = {2026},
author = {Thakkar, A and Mote, C and Gadade, A and Dighe, V and Kaur, G and Vora, A},
title = {Longifolene mitigates amyloid beta induced neurotoxicity by acting on PI3K/AKT/NFκB pathway: Comprehensive in vitro, in vivo pharmacokinetics and pharmacodynamic studies for Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179119},
doi = {10.1016/j.ejphar.2026.179119},
pmid = {42425385},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a multifactorial disease characterized with deposition of Amyloid-β peptide leading to oxidative stress and neuroinflammation. Terpenes are a broad class of natural compounds known to possess anti-oxidant and anti-inflammatory effects. Longifolene (LNF), a major constituent of pine resin is a non -polar sesquiterpene possessing promising anti-oxidant and anti-inflammatory activity. Oxidative stress and neuroinflammation are pathological drivers of AD. The current work is focused on evaluating the neuroprotective potential of LNF using in vitro cell line-based and in vivo animal-based model for AD. Pre-treatment with LNF at 1, 10 and 100 μM displayed significant neuroprotective potential in Aβ1-42 induced neurotoxicity in SH-SY5Y cell-line. Additionally, 0.5 and 1μM of LNF significantly prevented ROS generation, mitochondrial dysfunction and apoptosis in SH-SY5Y cell-line. Pharmacokinetic studies in rats showed that LNF achieved the therapeutic concentrations in brain. Further, in pharmacodynamic studies, 20 days pre-treatment and 30 days post-treatment with LNF at 10, 50 and 100 mg/kg resulted in dose-dependent improvements in behavioral, biochemical and histopathological parameters in Aβ1-42 induced AD in rats. Functional assays demonstrated that LNF brought about significant reduction in levels of AChE, TNF-α and IL-6 levels and elevation in BDNF in the rat brain. Histopathological examination of the cortex and hippocampus showed that LNF at doses of 50 and 100 mg/kg markedly attenuated neuronal swelling and cortical atrophic changes, while preserving the pyramidal layer thickness in the hippocampus. Protein expression studies using western blot analysis showed that LNF displays anti-AD activity by acting on PI3K/AKT/NFκB pathway. These findings highlight LNF as a potential neuroprotective agent for AD intervention.},
}

@article {pmid42413935,
year = {2026},
author = {Lee, S and Kao, CY and Li, Z and Dan, T and Wu, G and Hao, W},
title = {Optimal control for anti-abeta treatment in Alzheimer's disease using a reaction-diffusion model.},
journal = {Journal of the Royal Society, Interface},
volume = {23},
number = {240},
pages = {},
doi = {10.1098/rsif.2025.1158},
pmid = {42413935},
issn = {1742-5662},
support = {1R35GM146894/GF/NIH HHS/United States ; DMS-2533995//NSF/ ; DMS 2208373//NSF/ ; DMS 2513176//NSF/ ; //Huck Chair in AI Mathematical Modeling from Penn State University's Huck Institutes of the Life Sciences/ ; },
mesh = {*Alzheimer Disease/diagnostic imaging/metabolism/drug therapy/therapy ; Humans ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Models, Biological ; Positron-Emission Tomography ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that severely impairs survival and quality of life. While anti-amyloid beta (Aβ) therapies can slow disease progression, their efficacy depends on personalized dosing that maximizes benefits and minimizes risks, such as amyloid-related imaging abnormalities (ARIA). Mathematical modelling offers a powerful tool for understanding AD dynamics and optimizing treatment, yet most models focus solely on temporal behaviour, overlooking spatial heterogeneity within the brain. In this study, we propose a spatially explicit reaction-diffusion model to describe Aβ plaque dynamics. We formulate an optimal control problem to minimize plaque concentration while balancing therapeutic efficacy and treatment risk. Under reasonable assumptions, we establish well-posedness and uniqueness of the optimal solution. A finite element method (FEM)-based numerical framework is developed to compute personalized treatment strategies. Our model is calibrated using longitudinal Aβ positron emission tomography (PET) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), enabling estimation of patient-specific parameters, such as growth rate and effective diffusivity. Results show that optimized treatment strategies consistently outperform constant dosing regimens across patient groups, achieving substantial reductions in cumulative amyloid burden while minimizing side effects. This integrated, data-driven framework advances personalized, spatially informed therapeutic optimization for AD.},
}

*Alzheimer Disease/diagnostic imaging/metabolism/drug therapy/therapy
Humans
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Models, Biological
Positron-Emission Tomography

@article {pmid42415176,
year = {2026},
author = {Eom, JW and Kim, KR and Kim, DH and Song, JG and Han, C and Kim, HW and Ha, S and Song, WJ and Kim, YH},
title = {Zinc-mediated lysosomal activation by 1H10 enhances autophagy and attenuates tau pathology in Alzheimer's disease models.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01328-9},
pmid = {42415176},
issn = {1756-6606},
support = {NRF-2020R1I1A1A01061724//National Research Foundation of Korea/ ; RS-2023-NF001356//National Research Foundation of Korea/ ; 2025-RISE-01-019-04//The seoul RISE centor/ ; },
abstract = {Impaired autophagic flux and lysosomal dysfunction contribute critically to the accumulation of pathological protein aggregates in Alzheimer's disease (AD). Emerging evidence suggests that intracellular zinc dynamics regulate lysosomal function by modulating processes such as acidification and lysosomal biogenesis. We previously identified 1H10 as an AMP-activated protein kinase (AMPK) inhibitor and subsequently demonstrated its zinc-binding capacity and ability to regulate intracellular zinc homeostasis. Building on our prior findings that intra-lysosomal zinc promotes acidification and activates transcription factor EB (TFEB), we investigated whether 1H10 enhances lysosomal function through zinc mobilization in neurons, thereby improving autophagy and reducing pathological protein accumulation. In primary cortical neurons, 1H10 increased lysosomal abundance and enhanced lysosomal degradative capacity in a zinc-dependent manner, as demonstrated by increased cathepsin B activity and DQ-BSA degradation. It alleviated lysosomal dysfunction induced by v-ATPase inhibition and promoted autophagic flux, leading to reduced accumulation of amyloid-β (Aβ) and tau in neuronal models. In 5XFAD mice, 1H10 treatment showed trends toward improved spatial learning in the Morris water maze, reduced tau phosphorylation at Thr205 and Ser214, normalized LC3-II levels, and restored autophagic-lysosomal homeostasis, without significant changes in extracellular amyloid plaque burden. These findings indicate that zinc-mediated lysosomal activation by 1H10 enhances the autophagy-lysosomal pathway and attenuates tau pathology in AD models, suggesting that targeting lysosomal function may represent a potential therapeutic strategy for neurodegenerative disorders characterized by impaired proteostasis.},
}

@article {pmid42415281,
year = {2026},
author = {Aldana, BI and Freude, K},
title = {Chemokines in Alzheimer's Disease: Early Defence, Late Damage and the Impact of Sex and Infection.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {139},
number = {2},
pages = {e70273},
pmid = {42415281},
issn = {1742-7843},
support = {R434-2023-242//Lundbeck Foundation/ ; N/A//Alzheimersfonden/ ; },
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism ; *Chemokines/metabolism/immunology ; Animals ; Female ; Male ; Sex Factors ; Signal Transduction ; Virus Diseases/immunology ; Neuroinflammatory Diseases/immunology ; COVID-19/immunology ; Receptors, Chemokine/metabolism ; Brain/immunology/metabolism ; Sex Characteristics ; },
abstract = {Chemokines constitute a versatile signalling network maintaining homeostasis and glia-neuron communication in the healthy brain but become progressively dysregulated during aging and Alzheimer's disease (AD). This review examines how chemokine systems transition from tightly regulated homeostatic signals to drivers of chronic neuroinflammation in AD. We describe the major chemokine families (CC, CXC, CX3C) and their dominant central nervous system (CNS) receptors (CCR2, CXCR3, CX3CR1), which activate canonical inflammatory pathways including NF-κB, JAK/STAT and PI3K-AKT. In AD, chemokine dysregulation occurs in a coordinated manner across multiple functional modules, including recruitment-associated (CCL2, CXCL1), interferon-inducible (CXCL10), loss-of-restraint (CX3CL1) and vascular-associated chemokines. These alterations shift the network from regulated immune communication to self-sustaining inflammatory circuits perpetuating chronic neuroinflammation. These networks reprogram microglia and astrocytes into disease-associated phenotypes, amplify peripheral immune cell infiltration and destabilise synaptic function. Biological sex profoundly influences neuroinflammatory trajectories, with females exhibiting enhanced microglial senescence and interferon signalling, while males show accelerated complement activation. Viral pathogens, particularly neurotropic viruses (HSV-1, HHV-6, VZV) and SARS-CoV-2, actively reprogram chemokine networks, linking infection to amyloid-β accumulation, tau pathology and neurodegeneration. Therapeutically, chemokine axes represent precision targets requiring stage-matched, sex-stratified interventions rather than broad anti-inflammatory approaches. Understanding chemokine network dynamics offers mechanistic insights into AD pathogenesis and could provide pointers for therapeutic strategies.},
}

Humans
*Alzheimer Disease/immunology/metabolism
*Chemokines/metabolism/immunology
Animals
Female
Male
Sex Factors
Signal Transduction
Virus Diseases/immunology
Neuroinflammatory Diseases/immunology
COVID-19/immunology
Receptors, Chemokine/metabolism
Brain/immunology/metabolism
Sex Characteristics

@article {pmid42415688,
year = {2026},
author = {Hill, N and AlMuallim, HYO and Maddock, E and Hobbs, C and Clarke, E and Goncalves, MB and Corcoran, JPT},
title = {Treatment with KCL-286, a first-in-class retinoic acid receptor-β (RARβ) agonist, ameliorates neuronal DNA damage and inflammation in a mouse model of Alzheimer's disease.},
journal = {FEBS open bio},
volume = {},
number = {},
pages = {},
doi = {10.1002/2211-5463.70284},
pmid = {42415688},
issn = {2211-5463},
support = {110047/Z/15/Z/WT/WT_/Wellcome Trust/United Kingdom ; MR/R006466/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder for which effective disease-modifying therapies remain limited. Accumulation of neuronal DNA double-strand breaks (DSBs) is an early pathological event that contributes to genomic instability and neuronal vulnerability in AD. Therapeutic strategies that enhance DNA repair may therefore be of considerable interest. Here, using the Tg2576 mouse model of AD, we show that treatment with KCL-286, a selective retinoic acid receptor-β (RARβ) agonist, reduces neuronal DNA damage. KCL-286 enhances DSB repair in neurons, in part through upregulation of the DNA repair factor BRCA1, while also attenuating neuroinflammatory activation. In addition, KCL-286 normalises microglial and astrocytic morphology, consistent with reduced pathological glial activation. Together, these findings demonstrate that selective RARβ activation ameliorates neuronal DNA damage and neuroinflammation in a mouse model of AD, supporting further investigation as a potential disease-modifying therapeutic strategy.},
}

@article {pmid42415930,
year = {2026},
author = {Wang, PJ and Yang, XY and Ji, L and Shi, JJ and Cai, XM and Sun, P and Liu, HX and Jiang, F and Yang, F},
title = {Peripheral metabolomic profiling reveals lipid and amino acid alterations associated with immuno-inflammatory responses in treatment-naïve late-onset Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1858299},
pmid = {42415930},
issn = {1663-4365},
abstract = {BACKGROUND: Immuno-metabolic dysregulation contributes to Alzheimer's disease (AD) pathogenesis, yet the peripheral metabolic landscape and its interplay with neuroinflammation remain poorly characterized in treatment-naïve, late-stage patients. This study aimed to delineate plasma metabolic alterations and immuno-metabolic interactions in Chinese first-time outpatients with late-onset AD (CFTO-LOAD).

METHODS: Untargeted metabolomics and ELISA were applied to plasma from 35 CFTO-LOAD patients and 35 sex-matched cognitively healthy controls (CHCs) to quantify metabolites, cytokines (TNF-α, IL-17, IL-9), and soluble Aβ/Tau markers.

RESULTS: A total of 875 differentially abundant metabolites (DAMs) were identified in CFTO-LOAD, comprising 227 upregulated and 648 downregulated species (P < 0.05), predominantly lipids, fatty acids (e.g., dodecanoic acid, arachidonic acid), and amino acids (e.g., L-arginine, L-leucine). KEGG analysis revealed enrichment in fatty acid and amino acid metabolism, GABAergic synapse, and intestinal immune network pathways. CFTO-LOAD patients exhibited elevated pro-inflammatory cytokines TNF-α and IL-17 (P adj < 0.05), reduced IL-9 (P adj < 0.001), increased soluble p-Tau, p-Tau181, and p-Tau217 (P adj < 0.01), and decreased Aβ42/Aβ40 ratio (P adj < 0.001). Linear regression identified significant correlations between differential metabolites and immune/pathological markers, including positive associations of dodecanoic acid with TNF-α (r = 0.34, P adj < 0.05) and arachidonic acid with Aβ42/Aβ40 ratio (r = 0.30, P adj < 0.05), and negative associations of arachidonic acid with p-Tau217 (r = -0.43, P adj < 0.01) and sphinganine 1-phosphate with TNF-α (r = -0.28, P adj < 0.05).

CONCLUSION: These findings characterize the peripheral immuno-metabolic landscape in treatment-naïve late-onset AD, identifying metabolic mediators that may mechanistically link neuroinflammation to Aβ and Tau pathology. This provides a foundation for biomarker development and therapeutic targeting in late-stage disease, pending independent validation.},
}

@article {pmid42416049,
year = {2026},
author = {Yang, M and Liang, Z},
title = {GLP-1 receptor agonists in neurological diseases: mechanisms and therapeutic prospects from metabolism to neuroprotection.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1839620},
pmid = {42416049},
issn = {1664-3224},
mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy/metabolism ; Glucagon-Like Peptide-1 Receptor/metabolism ; *Neuroprotection/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used metabolic therapies for type 2 diabetes and obesity, with well-established cardiovascular benefits. Beyond glycemic control, accumulating experimental and clinical evidence suggests that GLP-1RAs exert pleiotropic actions relevant to neurological diseases. Metabolic dysfunction, chronic inflammation, oxidative stress, mitochondrial impairment, and neurovascular injury represent convergent mechanisms that contribute to neurodegeneration, cerebrovascular pathology, and metabolism-related brain disorders. Notably, these processes overlap with pathways modulated by GLP-1 signaling across systemic and central compartments. GLP-1 receptors are expressed in neurons, glial cells, and components of the neurovascular unit, providing a biological basis for possible neurological effects. Preclinical studies suggest that GLP-1RAs can reduce neuroinflammation and oxidative stress, support mitochondrial function, and help maintain blood-brain barrier integrity. Clinical findings, however, remain inconsistent. Studies in Parkinson's disease have reported encouraging signals, but biomarker evidence for disease modification is still limited. In Alzheimer's disease, clinical trials have produced mixed or negative results. These differences may reflect disease stage, patient selection, drug-specific pharmacology, central nervous system exposure, endpoint sensitivity, and treatment duration. Overall, GLP-1RAs may influence neurological disease through metabolic, inflammatory, and vascular pathways, but their clinical role remains unsettled. Future studies should use biomarker-informed designs, prespecified neurological endpoints, appropriate drug selection, and sufficiently long follow-up to determine which patients and disease stages are most likely to benefit.},
}

Humans
*Glucagon-Like Peptide-1 Receptor Agonists
Animals
*Neuroprotective Agents/therapeutic use/pharmacology
*Nervous System Diseases/drug therapy/metabolism
Glucagon-Like Peptide-1 Receptor/metabolism
*Neuroprotection/drug effects
Oxidative Stress/drug effects

@article {pmid42418270,
year = {2026},
author = {Caselli, RJ and Geldmacher, DS and Schilling, TB},
title = {A Narrative Review of Amyloid-β Monoclonal Antibodies for Alzheimer Disease: How Amyloid Species Engagement May Affect Clinical Outcomes.},
journal = {The neurologist},
volume = {31},
number = {4},
pages = {129-135},
pmid = {42418270},
issn = {2331-2637},
support = {//Eli Lilly and Company, Indianapolis, IN/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/immunology/metabolism ; *Antibodies, Monoclonal/therapeutic use ; Plaque, Amyloid/drug therapy ; Animals ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of death worldwide, with growing prevalence as life expectancy increases. An important neurological hallmark of AD is the deposition of extracellular neuritic amyloid-β (Aβ) plaques that can disrupt synaptic transmission and cause neuronal death. More recent studies suggest that targeting Aβ species can slow the progression of cognitive decline in AD.

REVIEW SUMMARY: This narrative review examines the efficacy of monoclonal antibodies targeting the amyloid-β (Aβ) protein in the treatment of AD. It discusses the mechanisms by which these antibodies aim to mitigate amyloid pathology and explores their clinical outcomes in various trials. The review highlights the importance of amyloid plaque reduction to less than 25 Centiloids observed through amyloid positron emission tomography (PET) scans as a predictor of slowing cognitive decline. The findings suggest that targeting insoluble amyloid plaques is crucial for achieving clinical benefits in AD treatment. This review also discusses the phenomenon of amyloid-related imaging abnormalities (ARIA) that may be associated with monoclonal antibody therapy.

CONCLUSION: Monoclonal antibodies that target Aβ monomers, soluble oligomers and protofibrils, and insoluble fibrils/plaques were developed, and not all have provided clinical benefit. Emerging evidence suggests that it is important to reduce amyloid plaque burden to less than 25 Centiloids, consistent with a visually negative amyloid PET scan, in order to slow cognitive decline in early symptomatic AD.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging/metabolism
*Amyloid beta-Peptides/immunology/metabolism
*Antibodies, Monoclonal/therapeutic use
Plaque, Amyloid/drug therapy
Animals

@article {pmid42418504,
year = {2026},
author = {Cai, Y and Wang, Y and Huang, W and Su, Y and Lei, M and Jia, R and Wu, C and Zhang, T and Sun, L and Peng, B and Cheng, J and Yu, J and Chen, X and Ye, Q and Yu, J and Xin, J},
title = {Lecanemab treatment improves B cell subpopulation immune homeostasis in patients with Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71655},
pmid = {42418504},
issn = {1552-5279},
support = {82571602//National Natural Science Foundation of China/ ; 82371188//National Natural Science Foundation of China/ ; 2022ZD0211603//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; ADB510200//Lingang Laboratory/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/immunology ; *Homeostasis/drug effects ; Female ; Male ; *B-Lymphocyte Subsets/drug effects/immunology ; Aged ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *B-Lymphocytes/drug effects/immunology ; Leukocytes, Mononuclear/drug effects ; },
abstract = {INTRODUCTION: Lecanemab, the first disease-modifying therapy for Alzheimer's disease (AD), mitigates pathology primarily by clearing amyloid plaques, but its impact on peripheral immunity remains unclear.

METHODS: To assess Lecanemab's immunological effects, we performed antibody array analysis of serum and single-cell RNA sequencing of peripheral blood mononuclear cells collected from healthy controls and patients with AD at baseline, 3, and 6 months post-treatment.

RESULTS: Lecanemab restored multiple serum chemokines to healthy levels in patients with AD. Compared to controls, baseline samples from patients with AD showed altered frequencies and functions of naïve and unswitched memory (UswM) B cells. Lecanemab treatment corrected the abnormal naïve and UswM B cell proportions and rebuilt their functional homeostasis by alleviating chronic inflammation and reversing the dysregulation of key pathways including immune response, NF-κB, RAGE, and cell adhesion.

DISCUSSION: These findings uncover a novel peripheral immunomodulatory mechanism of Lecanemab, offering new insights into AD therapeutics.},
}

Humans
*Alzheimer Disease/drug therapy/immunology
*Homeostasis/drug effects
Female
Male
*B-Lymphocyte Subsets/drug effects/immunology
Aged
*Antibodies, Monoclonal/therapeutic use/pharmacology
*B-Lymphocytes/drug effects/immunology
Leukocytes, Mononuclear/drug effects

@article {pmid42419633,
year = {2026},
author = {Cauzzi, E and Ficchì, S and De Paolis, ML and Saba, L and Montanari, M and Loffredo, G and La Barbera, L and Krashia, P and Nobili, A and D'Amelio, M},
title = {Midbrain dopamine loss drives parvalbumin interneuron vulnerability through tissue plasminogen activator-linked perineuronal-net breakdown and hippocampal disinhibition.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107527},
doi = {10.1016/j.nbd.2026.107527},
pmid = {42419633},
issn = {1095-953X},
abstract = {Midbrain dopaminergic degeneration is an early feature of Alzheimer's Disease (AD), dementia with Lewy bodies (DLB), and AD-Parkinson's disease overlap (AD-PD). However, its direct contribution to the failure of hippocampal inhibitory-circuits, a pathological feature shared across these conditions, remains unresolved. Parvalbumin-positive interneurons (PV-INs) regulate hippocampal excitation-inhibition balance and are directly modulated by dopamine (DA). These neurons are protected by perineuronal nets (PNNs), extracellular-matrix structures supporting fast GABAergic signaling and neuronal resilience. We tested whether midbrain-derived DA loss is sufficient to destabilize hippocampal PV-IN function, potentially promoting their vulnerability or affecting PNN integrity. Through stereotaxic unilateral 6-hydroxy-dopamine lesion of the Ventral Tegmental Area/Substantia Nigra pars compacta in C57BL/6 N mice, we reduced the hippocampal DA tone and midbrain-derived synaptic input onto PV-INs. At 1-month post-lesion, PV-IN numbers were preserved, but the PNN integrity was reduced, accompanied by increased expression of tissue plasminogen activator (tPA), a PNN-remodeling protease. In CA1 pyramidal neurons, spontaneous inhibitory postsynaptic currents showed reduced frequency with faster decay, and bicuculline unmasked heightened population-spike excitability. By 6-months post-lesion, PV-IN numbers declined significantly, especially in CA1, demonstrating progressive vulnerability. D2/D3 receptor (D2/D3R) activation with quinpirole normalized tPA levels in PV-INs ex vivo, restored PNN integrity after sub-chronic treatment in vivo and increased inhibitory postsynaptic-event frequency, indicating functional recovery of GABAergic drive. These findings support the involvement of a DA-D2/D3R-tPA axis contributing to PV-IN extracellular-matrix integrity and hippocampal inhibitory tone. They also demonstrate that DA depletion is sufficient to trigger PNN breakdown, reduce GABAergic inhibition, network hyperexcitability, and cause progressive PV-IN loss independently of canonical protein aggregates like Aβ, tau or α-synuclein, characteristic of AD, DLB or AD-PD. This mechanism links midbrain degeneration to hippocampal circuit failure, highlighting D2/D3R signaling and extracellular proteolysis as actionable targets for early circuit stabilization across AD, DLB, and AD-PD.},
}

@article {pmid42420256,
year = {2026},
author = {He, CY and Wang, XY and Fan, J and Wang, YN and Masters, CL and Wang, YJ},
title = {Could the cognitive benefits of amyloid-beta clearance grow in time for Alzheimer's disease?.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04188-y},
pmid = {42420256},
issn = {2158-3188},
support = {82588301//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82120108010//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82401695//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Alzheimer's disease (AD) is characterized histologically by amyloid-β (Aβ) deposition in the brain. Immunotherapies targeting Aβ clearance have become a leading treatment strategy. Although these therapies effectively reduce cerebral Aβ burden, their cognitive benefits remain modest during the trial period. This review systematically assesses the extent of Aβ clearance by immunotherapies and its related cognitive outcomes, focusing on whether cognitive benefits increase over time. We refine a model of the "lag effect" between plaque clearance and cognitive benefit, which is potentially influenced by clearance rate, treatment duration, disease stage, genetic factors, and aging. We also discuss the underlying biological mechanisms and potential neuroprotective targets. Future research should prioritize long-term studies, early intervention, personalized therapies, and combination approaches addressing multiple pathological pathways. Given limited short-term cognitive gains, optimizing outcomes will require tailoring treatments to individual patient factors-including genetics, disease progression, and aging-to minimize side effects and enhance long-term cognitive function.},
}

@article {pmid42420546,
year = {2026},
author = {Nour, H and Mounadi, N and Samadi, A and Chtita, S},
title = {Stylopine as multi-target anti-Alzheimer agent.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-61364-2},
pmid = {42420546},
issn = {2045-2322},
support = {#12R282//Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University/ ; },
abstract = {Alzheimer's disease is a complex neurodegenerative disorder involving multiple enzymes, such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), monoamine oxidase B (MAO-B), and β-secretase (BACE-1). Currently available treatments are limited to acetylcholinesterase inhibitors, which offer purely symptomatic relief and do not halt disease progression. Consequently, the development of multi-target ligands represents a promising therapeutic approach. In this study, Alkaloids were evaluated using in silico approaches. Predictions of biological activity performed using the PASS software revealed stylopine as a promising candidate with potential anti-Alzheimer activity. Furthermore, this compound demonstrated strong binding affinity for key targets (Torpedo AChE, BuChE, and BACE-1), as well as a promising pharmacokinetic profile. Molecular dynamics simulations and MM-GBSA calculations have demonstrated the stability of stylopine-target interactions. Taken together, these studies suggest that stylopine could be a promising multitarget agent for the treatment of Alzheimer's disease, although further experimental data are needed to confirm its efficacy.},
}

@article {pmid42421820,
year = {2026},
author = {Brosch, JR and Wang, S and Apostolova, LG and Agarwal, A and Allen, JW and Gutmann, L and Tobar, M and Gonzalez, L and Johnson, D and Treadway, L and Connolly, J and Tang, A and Lettich, E and Davies, S and Kuhn, N and Hammers, DB and Clark, D and Farlow, M and Willis, DR and Fowler, N and Wilcock, DM},
title = {The Indiana University Brain Health Program to deliver amyloid-targeted therapy to Alzheimer's disease patients.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70291},
pmid = {42421820},
issn = {2352-8737},
abstract = {INTRODUCTION: The Indiana University Brain Health Program was developed to support safe implementation of amyloid-targeting therapies (ATTs) for early Alzheimer's disease (AD).

METHODS: We established Neurology Brain Health Navigators (neuroBHNs) to extend our Brain Health Navigator model into specialty care. NeuroBHNs pre-screen patients for ATT eligibility, coordinate biomarker and imaging evaluation, provide structured education, and guide treatment initiation and monitoring. The program includes a dedicated social worker and insurance pre-authorization specialist to streamline infusion access. Blood pressure is monitored at each visit, and infusions are deferred if readings exceed 140/90 mmHg.

RESULTS: Through December 16, 2025, 243 patients initiated lecanemab therapy. Apolipoprotein E (APOE) ε4 homozygotes were not excluded; 74% of treated patients carried at least one Apoε4 allele. The ARIA rate was 13.2%, and 40% of patients experienced infusion-related reactions.

CONCLUSIONS: A navigator-centered model can efficiently deliver ATT while supporting structured education, screening, and safety monitoring, potentially contributing to favorable safety outcomes.},
}

@article {pmid42422111,
year = {2026},
author = {Wang, J and Fu, X and Liu, J and Yang, Y},
title = {Non-invasive brain stimulation in frontotemporal dementia: syndrome-specific signals and priorities for future trials.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1842455},
pmid = {42422111},
issn = {1663-4365},
abstract = {Frontotemporal dementia is the second most common cause of young-onset dementia after Alzheimer's disease and lacks disease-modifying treatment. This narrative review summarizes human studies of non-invasive brain stimulation, including repetitive transcranial magnetic stimulation and theta-burst stimulation, transcranial electrical stimulation, and transcranial photobiomodulation, in frontotemporal dementia and primary progressive aphasia. We review stimulation targets, protocols, outcomes, and safety, and organize the evidence by clinical subtype and modality. Current data remain preliminary, but recurrent signals support prefrontal and cerebellar repetitive transcranial magnetic stimulation/theta-burst stimulation and prefrontal or temporoparietal transcranial direct current stimulation, particularly in primary progressive aphasia. By contrast, controlled evidence in behavioral-variant frontotemporal dementia is limited and heterogeneous. Future trials should be sham-controlled, multicenter, and syndrome-stratified; combine stimulation with symptom-relevant cognitive or language therapy; and incorporate biomarker-informed targeting, target-engagement measures, and longer follow-up to determine durability and clinical relevance.},
}

@article {pmid42422228,
year = {2026},
author = {Sukreet, S and Donohue, MC and Ngolab, J and Belsha, A and Salazar, J and Cohen, P and Jaiswal, S and Tan, V and Aggarwal, NT and Alber, J and Johnson, K and Jicha, GA and van Dyck, CH and Ramanan, S and Lah, JJ and Salloway, S and Verdooner, SR and Rafii, MS and Aisen, PS and Sperling, RA and Rissman, RA},
title = {Relationships between longitudinal retinal amyloid imaging and amyloid PET in the A4 Trial.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70422},
pmid = {42422228},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is associated with retinal amyloid-related changes, which may help identify amyloid positron emission tomography (PET) positive (+) individuals. Previously, in a small cross-sectional study, we reported higher retinal spot counts (RSCs) in preclinical amyloid PET (+) individuals screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial compared to control individuals enrolled in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) trial before drug treatment.

METHODS: Eligible volunteers had retinal scans 48 hours after consuming curcumin. Scans were processed and quantified via NeuroVision. Participants were grouped by amyloid status and treatment to assess the effect of solanezumab on RSC.

RESULTS: RSC did not differ significantly over time between groups and was not modified by treatment, diverging from the cross-sectional retinal amyloid findings observed in A4/LEARN.

DISCUSSION: Curcumin-based retinal amyloid labeling shows promise but needs standardized protocols and validation in larger cohorts to understand its relationship to amyloid PET.},
}

@article {pmid42422260,
year = {2026},
author = {Akhbari, M and Babaei, F and Navidi-Moghaddam, A and Ghafghazi, S and Khodabandehloo, F and Sarookhani, MR and Dargahi, L and Mohammadi, G and Nassiri-Asl, M},
title = {The effects of Saccharomyces boulardii on TLR4/NF-κB neuroinflammatory pathway in the hippocampus of LPS-induced rats.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {199-206},
pmid = {42422260},
issn = {2667-2421},
abstract = {Saccharomyces boulardii (Sb), a probiotic yeast, is known for its positive effects on gastrointestinal and metabolic health. Recent research has explored its potential to influence neurological conditions by modulating neuroinflammatory responses via the gut-brain axis. Toll-like receptor 4 (TLR4) is recognized as a key molecular target in regulating neuroinflammation, particularly in disorders like Alzheimer's disease (AD). This study investigated whether Sb could alleviate downstream elements of the TLR4 neuroinflammatory pathway in a lipopolysaccharide (LPS)-induced rat model relevant to AD. Rats were randomly assigned to four groups: 1) control, 2) LPS, 3) Sb + LPS, and 4) Sb alone. All groups received either normal saline or Sb (a volume of 1 ml containing 10 [10] CFU) by oral gavage for four weeks. From day 14, LPS (250 μg/kg/day) or saline was administered intraperitoneally for nine days. Researchers assessed spatial memory, levels of TLR4 pathway-associated proteins in the hippocampus, pro-inflammatory cytokine expression, and neuronal survival using Nissl staining. The results showed that pre-treatment with Sb partially ameliorated spatial learning deficits, significantly reducing the LPS-induced elevation of nuclear factor kappa B (NF-κB) and interleukin-1β (IL-1β) in the hippocampus and protecting against neuronal loss in the hippocampal CA1 region. Sb mitigates LPS-induced neuroinflammation by modulating downstream elements of the TLR4 pathway-specifically NF-κB and IL-1β-rather than acting directly on the TLR4 receptor, likely through mechanisms involving the gut-brain axis.},
}

@article {pmid42411221,
year = {2026},
author = {Sharma, A and Kaur, A and Khan, J and Pandey, H},
title = {Phyto-Nanotherapeutics for Alzheimer's Disease: Current Progress and Future Perspectives.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249455878260609100548},
pmid = {42411221},
issn = {1875-6166},
abstract = {Alzheimer's Disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive and behavioral impairment and represents a major cause of dementia worldwide. It primarily affects the elderly population. The disease is marked by progressive neuronal damage, leading to impairments in cognition, behavior, emotions, and communication. Although currently available therapies provide symptomatic relief, they fail to alter disease progression, necessitating the development of more effective therapeutic strategies. Phytoconstituents have gained considerable attention due to their neuroprotective properties and multitargeted mechanisms of action against pathways implicated in AD. However, their clinical application is limited by poor Blood-Brain Barrier (BBB) permeability, low bioavailability, and inadequate solubility. Nanotechnology offers a promising approach for brain-targeted drug delivery by enhancing the therapeutic efficacy of phytoconstituents through advanced nanocarrier systems. This review explores the synergistic potential of phytoconstituents and nanocarriers for the management of AD, aiming to improve therapeutic outcomes and overcome existing limitations. It further highlights the integration of medicinal plant-based compounds with nanotechnology as a novel strategy for AD treatment. The combination of nanocarriers and phytoconstituents may facilitate enhanced BBB penetration and improved neuroprotection. Notably, nanomedicine- based approaches, including phytoconstituent-loaded nanoparticles and liposomes, demonstrate significant potential to overcome delivery barriers and enable efficient drug transport to the brain.},
}

@article {pmid42411440,
year = {2026},
author = {Ye, T and Shuai, Y and Liu, Y and Liu, S and Tang, X and Tian, W and Zhang, Y and Kong, Y},
title = {Efficacy and Safety of Transcranial Direct Current Stimulation on Multiple Health Outcomes in Neurological Disorders: An Umbrella Review of Meta-Analyses of Randomized Controlled Trials.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {6},
pages = {47145},
doi = {10.31083/JIN47145},
pmid = {42411440},
issn = {0219-6352},
mesh = {*Transcranial Direct Current Stimulation ; Humans ; *Nervous System Diseases/therapy ; *Randomized Controlled Trials as Topic ; Meta-Analysis as Topic ; Systematic Reviews as Topic ; *Outcome Assessment, Health Care/statistics & numerical data ; },
abstract = {BACKGROUND: Neurological disorders are a leading cause of disability worldwide. Transcranial direct current stimulation (tDCS) is a promising therapeutic tool for neurological disorders. However, a consensus on clinical recommendations for using tDCS in patients with neurological disorders is lacking. In this umbrella review, we aimed to establish evidence-based guidance for using tDCS to treat neurological disorders.

METHODS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 2020. PubMed/MEDLINE, Embase, the Cochrane Library, the Web of Science, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) were systematically searched to identify and evaluate existing systematic reviews and meta-analyses on the use of tDCS for neurological disorders. Quality was assessed using the Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) and the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. The Hartung-Knapp-Sidik-Jonkman random effects model was employed for reanalysis.

RESULTS: A total of 17 systematic reviews and meta-analyses encompassing 358 randomized controlled trials and 7160 participants were analyzed. tDCS demonstrated efficacy across seven distinct health conditions, including stroke, Parkinson's disease, Alzheimer's disease, cerebellar ataxia, fibromyalgia, disorders of consciousness, and migraine. Adverse effects were rarely reported, with the exception of mood changes associated with fibromyalgia. Our results indicated that tDCS significantly improved 34 distinct health outcomes related to these conditions.

CONCLUSIONS: We found that tDCS may be a promising treatment for neurological disorders, with mild and infrequent adverse effects. Further studies are warranted to validate the therapeutic potential of tDCS in the reported neurological conditions, investigate additional neurological health outcomes, and explore the underlying mechanisms of tDCS effects. The PROSPERO Registration: CRD42024589432, https://www.crd.york.ac.uk/PROSPERO/view/CRD42024589432.},
}

*Transcranial Direct Current Stimulation
Humans
*Nervous System Diseases/therapy
*Randomized Controlled Trials as Topic
Meta-Analysis as Topic
Systematic Reviews as Topic
*Outcome Assessment, Health Care/statistics & numerical data

@article {pmid42411945,
year = {2026},
author = {Nakamura, Y and Tsushio, T and Tanahashi, M and Suganami, H and Omori, T and Nishiyama, K and Aoki, H and Nagakura, N},
title = {Post Hoc Subgroup Analysis by Disease Severity in a Non-Inferiority Trial of Donepezil 27.5 mg Transdermal Formulation in Japanese Patients With Mild-to-Moderate Alzheimer Disease.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000738},
pmid = {42411945},
issn = {1546-4156},
support = {//Teikoku Seiyaku/ ; },
abstract = {BACKGROUND: The efficacy of cholinesterase inhibitors varies depending on the severity of Alzheimer disease. We examined the effects of the disease severity on the efficacy of donepezil 27.5 mg patches in Japanese patients with Alzheimer disease.

METHODS: A post hoc analysis of covariance using per-protocol set in a noninferiority study of donepezil 27.5 mg patches with donepezil hydrochloride 5 mg tablets (JapicCTI-194582) was conducted after imputation of missing data using multiple imputations.

RESULTS: No apparent imbalances in the extracted confounding factors were observed between the 2 treatment groups. The baseline value of the Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale was adjusted using analysis of covariance. Least-squares mean of changes from baseline in the Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale at week 24 for each group were -1.661 (-2.681 to -0.640) (donepezil patch) and 0.065 (-0.987 to 1.117) (donepezil hydrochloride tablet). The difference in the least-squares mean (95% CI) between 2 groups was -1.726 (-3.1913 to -0.2602, P=0.021).

CONCLUSIONS: A post hoc analysis of covariance using the per-protocol set suggested that donepezil patches may be more effective than donepezil tablets in slowing cognitive decline in patients with mild Alzheimer disease.},
}

@article {pmid42412004,
year = {2026},
author = {Zhang, J and Wang, Y and Lu, Z and Yang, Y and Wang, J and Zhao, L and Li, F and Miao, M and Chen, WM and Wu, SY and Sun, M},
title = {HbA1c trajectories after SGLT2 inhibitor initiation and the risk of dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261462927},
doi = {10.1177/13872877261462927},
pmid = {42412004},
issn = {1875-8908},
abstract = {BackgroundType 2 diabetes mellitus (T2DM) is a major risk factor for dementia, yet the prognostic value of early dynamic glycemic changes following glucose-lowering therapy remains underinvestigated.ObjectiveTo determine whether early glycated hemoglobin (HbA1c) trajectories after initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i) predict long-term dementia and mortality risks.MethodsThis retrospective new-user cohort study utilized electronic health records from the TriNetX Global Network. Adults with T2DM initiating their first SGLT2i were included. To mitigate immortal-time bias, a 1-year landmark design was applied. Patients were stratified by baseline HbA1c and classified into improved, stable, or worsened trajectories based on values 91-455 days post-initiation. Propensity-score matching was performed within strata. The primary outcome was all-cause dementia.ResultsAmong 172,050 matched patients, modest HbA1c worsening in those with Good baseline control (<7.0%) did not increase dementia risk (HR 0.93; 95% CI, 0.75-1.15). However, in patients with Fair baseline control (7.0-8.9%), worsening to Poor control significantly increased dementia (HR 1.39; 95% CI, 1.11-1.74) and mortality risks. Conversely, among those with Poor baseline control (≥9.0%), trajectory improvement conferred substantial neuroprotection, reducing the risk of dementia (HR 0.64; 95% CI, 0.51-0.79) and mortality (HR 0.71; 95% CI, 0.60-0.84). These findings provide clinically actionable evidence linking glycemic dynamics to neurodegenerative risk, particularly Alzheimer's disease and related dementias.ConclusionsDynamic HbA1c trajectories following SGLT2i initiation independently predict dementia risk. Integrating trajectory-based assessments into routine care provides an actionable, scalable biomarker to guide timely treatment intensification and mitigate diabetes-related neurocognitive decline.},
}

@article {pmid42412302,
year = {2026},
author = {Zhang, C and Ma, Y and Shi, Z and He, X and Hu, J and Chen, S and Wu, H and Tian, M and Yan, C and Xing, M and He, L},
title = {Study on the Effects and Mechanisms of Resveratrol in Improving Cognitive Impairment in Aβ1-42-Induced Alzheimer's Disease Model Mice.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42412302},
issn = {1557-1904},
mesh = {Animals ; *Resveratrol/pharmacology/therapeutic use ; *Alzheimer Disease/chemically induced/drug therapy/metabolism ; *Amyloid beta-Peptides/toxicity ; Mice ; *Peptide Fragments/toxicity ; *Cognitive Dysfunction/drug therapy/chemically induced/metabolism ; Disease Models, Animal ; Male ; Autophagy/drug effects ; Mice, Inbred C57BL ; *Antioxidants/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; },
abstract = {Aging is a major risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). Targeting cellular senescence has therefore emerged as a promising therapeutic strategy. Resveratrol (RV), a natural polyphenolic compound, exhibits anti-aging properties through the regulation of autophagy and oxidative stress; however, its mechanisms in AD remain incompletely understood. In this study, we investigated the effects and underlying mechanisms of RV in an Aβ1-42-induced AD model. In vivo, RV administration significantly reduced the expression of aging-related markers and activated autophagy-associated signaling pathways. In vitro, RV treatment markedly attenuated Aβ1-42-induced cell viability loss and excessive reactive oxygen species (ROS) production. Further mechanistic analyses demonstrated that RV-induced autophagy activation was closely associated with the AMP-activated protein kinase/UNC-51-like kinase 1 (AMPK/ULK1) and silent information regulator 1/nuclear factor-kappaB (SIRT1/NF-κB) pathways. Collectively, these findings suggest that RV alleviates AD-related pathological processes by promoting autophagy and delaying cellular senescence, highlighting its potential as a therapeutic agent for age-related neurodegenerative diseases.},
}

Animals
*Resveratrol/pharmacology/therapeutic use
*Alzheimer Disease/chemically induced/drug therapy/metabolism
*Amyloid beta-Peptides/toxicity
Mice
*Peptide Fragments/toxicity
*Cognitive Dysfunction/drug therapy/chemically induced/metabolism
Disease Models, Animal
Male
Autophagy/drug effects
Mice, Inbred C57BL
*Antioxidants/pharmacology/therapeutic use
Oxidative Stress/drug effects

@article {pmid42412614,
year = {2026},
author = {Duan, W and Xing, Y and Liu, W},
title = {Protocol for generating multiplexed prime-edited monoclonal cell lines in porcine fetal fibroblasts.},
journal = {STAR protocols},
volume = {7},
number = {3},
pages = {104691},
doi = {10.1016/j.xpro.2026.104691},
pmid = {42412614},
issn = {2666-1667},
abstract = {Porcine fetal fibroblasts (PFFs) serve as standard donor cells for generating cloned pigs, and prime editing (PE) enables precise genome modification. Here, we describe a protocol for generating multiplexed prime-edited monoclonal cell lines in PFFs. We describe steps for pegRNA/ngRNA design and screening, plasmid electroporation, nocodazole treatment, puromycin selection, and monoclonal isolation and genotyping. Although demonstrated by introducing three Alzheimer's disease-associated pathogenic mutations, the pipeline can be readily adapted to multiplex PE of other endogenous loci in porcine cells. For complete details on the use and execution of this protocol, please refer to Liu et al.[1].},
}

@article {pmid42412645,
year = {2025},
author = {Hidasi, Z and Fullajtár, M},
title = {[Special aspects of the treatment of Alzheimer's disease (Anti-amyloid therapies and management of BPSD)].},
journal = {Psychiatria Hungarica : A Magyar Pszichiatriai Tarsasag tudomanyos folyoirata},
volume = {40},
number = {3-4},
pages = {274-281},
pmid = {42412645},
issn = {0237-7896},
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology/therapy ; *Amyloid beta-Peptides/immunology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Immunization, Passive ; },
abstract = {Due to its diverse symptomatology, Alzheimer's disease requires a complex therapeutic approach. Among the disease-modifying pharmacotherapeutic options, significant progress has recently been made in the field of anti-amyloid antibody therapies. These are generally costly procedures in which passive immunization targets various components of the beta-amyloid cascade. The individual agents differ significantly in terms of efficacy and potential side effects/complications. Considering the questionable degree of cognitive effectiveness, and the associated risks, the exact evaluation of the practical applicability of these agents is currently not possible; long-term data analysis is needed. The symptom cluster of behavioral and psychological symptoms of dementia (BPSD) is in itself complex, encompassing a wide range of clinical phenomena. These symptoms, which frequently occur in everyday patient care and often have multifactorial origins and pathomechanisms, require a complex therapeutic approach. The therapeutic benefit of pharmacological treatments applicable to specific symptom clusters is often difficult to determine due to potential side effects; therefore, individualized treatment supplemented with non-pharmacological methods is warranted. Keywords: Alzheimer's disease; anti-amyloid therapies; behavioral and psychological symptoms of dementia (BPSD).},
}

Humans
*Alzheimer Disease/drug therapy/psychology/therapy
*Amyloid beta-Peptides/immunology
Antibodies, Monoclonal, Humanized/therapeutic use
Immunization, Passive

@article {pmid42413499,
year = {2026},
author = {Vear, A and Olsen, SA and Lange, ECH and Müller, MA and Svendsen, C and Clemmensen, C},
title = {Preventative semaglutide and tirzepatide treatment does not alter disease progression in the 5xFAD mouse model of Alzheimer's disease.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102906},
doi = {10.1016/j.xcrm.2026.102906},
pmid = {42413499},
issn = {2666-3791},
abstract = {There is growing evidence that long-acting mimetics of the gut-derived incretin hormones GLP-1 and GIP act as disease-modifying therapies for Alzheimer's disease (AD). Here, we temporally characterize the efficacy of the approved incretin receptor agonists semaglutide, a GLP-1R agonist, and tirzepatide, a GLP-1R/GIPR co-agonist, in preventing AD progression. In 5xFAD mice treated for 2 or 4 months, both incretin therapies lower body weight and improve glucose tolerance, yet neither compound produces measurable effects on memory or learning tasks, amyloid-β plaque deposition, or glial cell activation. In a non-amyloidogenic model, 3 days of incretin pre-treatment does not alter microglial activation or the expression of inflammatory markers following lipopolysaccharide (LPS) administration in mice. Our findings indicate that chronic semaglutide or tirzepatide treatment, even when initiated before overt pathology and delivered for a prolonged period, does not slow neuropathological progression in 5xFAD or LPS-treated mice.},
}

@article {pmid42413719,
year = {2026},
author = {Alameen, AAM and Al-Kuraishy, HM and Abdelaziz, AM and Al-Gareeb, AI and Albuhadily, AK and Batiha, GE},
title = {Targeting PARP1-dependent parthanatos in Alzheimer's disease: Mechanisms and therapeutic opportunities.},
journal = {Life sciences},
volume = {402},
number = {},
pages = {124578},
doi = {10.1016/j.lfs.2026.124578},
pmid = {42413719},
issn = {1879-0631},
abstract = {Alzheimer's disease (AD) is the predominant cause of dementia globally. This review clarifies the dual function of poly(ADP-ribose) polymerase 1 (PARP1) in AD pathogenesis, emphasizing its role in mediating parthanatos, a unique caspase-independent cell death mechanism. We analyze contemporary literature regarding PARP1 expression, parthanatos signaling, and pharmaceutical treatments in AD models. In addition, PARP1 exhibits context-dependent duality: its physiological nuclear expression in hippocampus neurons is essential for memory consolidation and decreases early in cognitive impairment, suggesting a correlative association with synaptic malfunction. In contrast, overactivity of PARP1 resulting from Aβ-induced oxidative stress and DNA damage induces neurodegeneration via multiple pathways, including NAD+/ATP exhaustion leading to metabolism collapse, creation of the AIF-MIF complex promoting parthanatos, NF-κB-induced neuroinflammation, dysregulation of mitophagy, and disruption of the neuroprotective SIRT1 signaling pathway. The overactivity contributes to a positive feedback loop, where PARP1 intensifies Aβ and tau protein accumulation while simultaneously disrupting the BBB. In preclinical models of AD, genetic knockout, pharmacologic agents such as PJ34 and MC2050, or precursors of NAD[+] such as nicotinamide and NMN attenuate Aβ deposition, normalize metabolism, and ameliorate cognitive decline. The PARP1/parthanatos pathway is at the center of the confluence of oxidative stress, DNA damage, metabolism disorder, and neuroinflammation in AD. Metformin and other PARP1 inhibitors offer intriguing treatment options. PARP1's cell-type- and intracellular location-dependent activity necessitates careful consideration of context, dose, and disease stage while developing therapies. The present understanding in this review could inform future research on PARP1 regulation in AD clinical practice.},
}

@article {pmid42403709,
year = {2026},
author = {Fontán-Baselga, T and Cañeque-Rufo, H and Rivera-Illades, E and Gramage, E and Zapico, JM and de Pascual-Teresa, B and Ramos-Álvarez, MDP and Vicente-Rodríguez, M and Herradón, G},
title = {Chronic inhibition of receptor protein tyrosine phosphatase β/ζ reduces amyloid plaque load and modulates pleiotrophin-expressing glial cells, glial-plaque interactions and genes related to amyloid beta clearance.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1839516},
pmid = {42403709},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia. Pleiotrophin (PTN) is a neurotrophic factor relevant for central nervous system repair, neuron differentiation and survival. It is upregulated in different neuroinflammatory conditions. PTN is an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ. In a previous study, we showed that a short treatment with the RPTPβ/ζ inhibitor MY10 reduced amyloid beta (Aβ) plaque formation and glial activation in old APP/PS1 mice. Nevertheless, these preliminary data required new studies to prove the disease-modifying potential of RPTPβ/ζ inhibition by using younger animals and a longer treatment with MY10. Thus, we have now treated for 3 months five- to seven-month-old wild type (WT) and APP/PS1 mice with MY10. This treatment decreased Aβ plaque formation and increased the number of microglial cells in the dorsal subiculum of APP/PS1 mice. In addition, MY10 reduced the number of GFAP+, not Iba1+, cells surrounding Aβ plaques. As expected, PTN expression was upregulated in the brain of APP/PS1 compared to WT mice and it was mainly found in Iba1+ and GFAP+ cells. Interestingly, treatment with MY10 significantly decreased the expression of PTN and the number of PTN-expressing Iba1+ and GFAP+ cells. MY10 induced a significant decrease of Mmp9 expression in the hippocampus of APP/PS1 mice, a key enzyme in AD progression. In summary, chronic inhibition of RPTPβ/ζ in APP/PS1 mice reduces Aβ plaque deposition, modulating glial-plaque interactions and the expression of specific genes including Ptn and its receptor.},
}

@article {pmid42403869,
year = {2026},
author = {Tuleubayeva, A},
title = {Cardiovascular Biomarkers as a Primary Care Gateway to Early Alzheimer's Disease Detection: The Case for an Integrated Screening Approach.},
journal = {Cureus},
volume = {18},
number = {6},
pages = {e110287},
pmid = {42403869},
issn = {2168-8184},
abstract = {Alzheimer's disease (AD) affects millions of Americans and represents one of the leading causes of disability and healthcare expenditure in the United States. The vast majority of patients are diagnosed at the symptomatic stage, when substantial neuronal loss has already occurred and the therapeutic window for disease-modifying treatment has closed. Recently approved disease-modifying therapies have created an urgent clinical need for pre-symptomatic patient identification. The cardiovascular risk factors most commonly managed in primary care -- hypertension, dyslipidemia, type 2 diabetes, atrial fibrillation, and chronic heart failure -- are among the most powerful modifiable antecedents of AD pathology, operating through systemic inflammation, cerebral small vessel disease, impaired glymphatic clearance, and tau hyperphosphorylation. The biomarkers used to monitor these conditions -- C-reactive protein, cardiac troponin, NT-proBNP, and homocysteine -- reflect active neurodegeneration risk processes already measured routinely in primary care. This clinical perspective proposes a three-stage integrated neuro-cardiological screening protocol linking cardiovascular biomarker assessment to plasma P-tau217 blood testing for AD confirmation. This framework addresses the implementation gap identified in recent United States primary care literature and represents a practical step toward closing the AD diagnostic gap.},
}

@article {pmid42404289,
year = {2026},
author = {Larson, ST and Susman, JL},
title = {Navigating Alzheimer's Disease in Primary Care: Practical Strategies for Diagnosis and Management.},
journal = {International journal of general medicine},
volume = {19},
number = {},
pages = {603347},
pmid = {42404289},
issn = {1178-7074},
abstract = {Alzheimer's disease (AD), the most common form of dementia, is a neurodegenerative disorder that primarily affects older adults. Because the number of Americans 65 years of age and older living with AD is expected to increase and the availability of specialty physicians, such as neurologists and geriatricians, is limited, the role of primary care in diagnosing and managing patients with AD is expected to grow. Several guidelines for primary care providers are available for the evaluation, diagnosis, and treatment of patients with AD. However, there is no single concise and convenient reference tool for use in the primary care setting. In the primary care setting, clinicians are responsible for identifying patients at risk or demonstrating signs of cognitive impairment, administering cognitive tests, identifying appropriate referrals, and, in some cases, ordering blood-based biomarker testing. Although definitive testing and treatment identification may occur in the specialty care setting, in addition to serving as the hub to coordinate the multidisciplinary care team, primary care clinicians remain responsible for guiding patients and caregivers through shared decision-making regarding treatment, as well as the myriad responsibilities related to comorbidities, patient and caregiver psychological well-being, social support, and safety. This review aims to provide practical recommendations to primary care clinicians for the diagnosis, management, and long-term care of patients with AD.},
}

@article {pmid42404421,
year = {2025},
author = {Mansouri, Z and Motamedi, F and Khodagholi, F and Zahmatkesh, M},
title = {Histone Deacetylase Class IIb Inhibition Improves Amyloid-β-induced Learning and Memory Deficits in Male Rats.},
journal = {Basic and clinical neuroscience},
volume = {16},
number = {3},
pages = {583-594},
pmid = {42404421},
issn = {2008-126X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease associated with progressive impairment of cognitive function. The primary pathological features of AD include aggregation of amyloid-β (Aβ) and hyperphosphorylation of the tau protein. Histone deacetylases (HDACs) play a crucial role in the pathophysiology of neurodegenerative diseases. This study aimed to investigate the potential neuroprotective effects of HDAC6 and HDAC10 inhibition in a rodent model of AD.

METHODS: Learning and memory deficits were induced by bilateral intra-hippocampal Aβ injections in male Wistar rats. Tubacin (HDAC6 inhibitor) and bufexamac (HDAC6 and 10 inhibitors) were microinjected 30 minutes after Aβ injection. The possible molecular changes in the hippocampus following Aβ injection were also assessed by western blotting analysis of pCREB/CREB and Pp70/P70 ratios.

RESULTS: Our results revealed that bufexamac significantly recovered learning and memory impairments induced by Aβ in the Morris water maze (MWM) task. Tubacin improved memory decline without affecting learning. Bilateral intra-hippocampal injection of each of the HDAC inhibitors significantly increased the pCREB/CREB and Pp70/p70 ratios compared to the Aβ group, which was concurrent with behavioral alterations.

CONCLUSION: HDAC IIb treatment may be a promising strategy for improving learning and memory impairments in an animal model of AD, suggesting that HDAC targeting is a valuable strategy for further investigation.},
}

@article {pmid42404899,
year = {2026},
author = {Oh, SJ and Shin, OS and Hur, JY},
title = {From infection to dysfunction: viral triggers and antiviral immune factors in Alzheimer's disease pathology.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1839357},
pmid = {42404899},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/pathology/virology ; Animals ; *Virus Diseases/immunology ; Brain/immunology/virology/pathology ; Host-Pathogen Interactions/immunology ; SARS-CoV-2/immunology ; },
abstract = {Neurodegenerative diseases and neurocognitive disorders increasingly appear to share a common and underappreciated contributor: the viral-immune axis in the brain. This review presents current evidence linking neurotropic viruses and host antiviral immunity to the onset and progression of neurodegeneration and neurocognitive dysfunction. We explore how viral infections, particularly by Herpesviruses, Severe Acute Respiratory Syndrome Coronavirus 2, and Human Immunodeficiency Virus, disrupt neural homeostasis through neuroinflammation, amyloidosis, tauopathy, and autophagy dysregulation in neurodegeneration including Alzheimer's disease (AD). Simultaneously, host antiviral mechanisms, including type I interferons and interferon regulatory factors, often amplify neuronal damage when dysregulated. By examining viral and immune interactions within the neurodegenerative diseases, this review aims to broaden our understanding of the viral-immune axis in the brain and inspire novel approaches to prevention and treatment.},
}

Humans
*Alzheimer Disease/immunology/pathology/virology
Animals
*Virus Diseases/immunology
Brain/immunology/virology/pathology
Host-Pathogen Interactions/immunology
SARS-CoV-2/immunology

@article {pmid42406171,
year = {2026},
author = {Wu, H and Xia, J and Shi, Z and Zhang, C and Chen, S and Dai, L and He, L},
title = {Vorinostat Rescues Cognitive Deficits in a Neuroinflammatory Mouse Model: A Study of Sex Differences and the Underlying TLR4/NF-κB Mechanism.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42406171},
issn = {1573-6903},
mesh = {Animals ; *Toll-Like Receptor 4/metabolism ; Male ; *Vorinostat/therapeutic use/pharmacology ; Female ; *NF-kappa B/metabolism ; Mice, Inbred C57BL ; Mice ; *Neuroinflammatory Diseases/drug therapy/metabolism/chemically induced ; Lipopolysaccharides ; *Sex Characteristics ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; Signal Transduction/drug effects ; Microglia/drug effects/metabolism ; Neuroprotective Agents/therapeutic use/pharmacology ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Histone Deacetylase Inhibitors/therapeutic use/pharmacology ; },
abstract = {With the acceleration of global aging, Alzheimer's disease (AD) poses a significant public health challenge, and effective treatments are still lacking. Neuroinflammation, particularly microglia-mediated inflammation, plays a central role in AD pathogenesis, with the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway being a key regulator. The histone deacetylase inhibitor (HDACi) Vorinostat (SAHA) has shown anti-inflammatory and neuroprotective potential in preclinical studies. Given the significant sex differences in AD incidence, pathology, and treatment response, this study aimed to systematically investigate the effects of SAHA on lipopolysaccharide (LPS)-induced neuroinflammation and cognitive dysfunction, analyzing its sex-specific effects and underlying mechanisms. An LPS-induced neuroinflammation model was established in male and female C57BL/6 mice via intraperitoneal injection (1 mg/kg) for 7 consecutive days, followed by SAHA (50 mg/kg) gavage intervention for 23 days. Cognitive function was assessed using Y-maze, novel object recognition, and passive avoidance tests. Hippocampal pathology was analyzed via hematoxylin-eosin (HE) staining and Nissl staining. Western blot and quantitative PCR (qPCR) were used to detect hippocampal expression of the TLR4/TRAF6/IKKα/NF-κB pathway, inflammatory factors (IL-6, IL-1β, TNF-α, iNOS), and neuroplasticity-related proteins (BDNF, p-CREB). In vitro experiments using LPS-stimulated BV2 microglia validated SAHA's anti-inflammatory mechanisms via CCK-8, Griess assay, qPCR, and Western blot. Results showed that LPS treatment significantly activated the TLR4/TRAF6/IKKα/NF-κB pathway, upregulated hippocampal pro-inflammatory factors, caused neuronal damage, and impaired learning and memory; these effects appeared more pronounced in female mice, though this observation is exploratory and requires cautious interpretation. SAHA treatment markedly alleviated LPS-induced inflammation, neuropathology, and cognitive deficits. Notably, SAHA appeared to produce differential effects across sexes: female mice showed potentially stronger and more comprehensive improvements in cognitive recovery, downregulation of inflammatory factors, and upregulation of BDNF and p-CREB compared to males, suggesting a possible sexually dimorphic response. In vitro experiments further confirmed that SAHA significantly reduced inflammation in LPS-stimulated BV2 microglia by inhibiting the TLR4/TRAF6/IKKα/NF-κB pathway. In conclusion, this study demonstrates that SAHA exerts neuroprotective effects by inhibiting the TLR4/NF-κB pathway, thereby improving cognitive impairment, and may have a more pronounced protective effect in females. These findings suggest SAHA is a promising drug for treating neuroinflammation-induced cognitive dysfunction and highlight the importance of considering sex as a biological variable in epigenetic therapy for precision medicine.},
}

Animals
*Toll-Like Receptor 4/metabolism
Male
*Vorinostat/therapeutic use/pharmacology
Female
*NF-kappa B/metabolism
Mice, Inbred C57BL
Mice
*Neuroinflammatory Diseases/drug therapy/metabolism/chemically induced
Lipopolysaccharides
*Sex Characteristics
*Cognitive Dysfunction/drug therapy/metabolism/chemically induced
Signal Transduction/drug effects
Microglia/drug effects/metabolism
Neuroprotective Agents/therapeutic use/pharmacology
Disease Models, Animal
Hippocampus/drug effects/metabolism
Histone Deacetylase Inhibitors/therapeutic use/pharmacology

@article {pmid42406553,
year = {2026},
author = {Wen, S and Gao, J and Wang, Z and Ma, Q and Xu, XL and Chen, J},
title = {EphB1-Mediated Transient Blood-Brain Barrier Opening Facilitates a Ferritin-Based Nanotherapeutic for Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76480},
doi = {10.1002/advs.76480},
pmid = {42406553},
issn = {2198-3844},
support = {ZKJC2203//Zhejiang Rehabilitation Medical Center/ ; ZKXK02//Zhejiang Rehabilitation Medical Center/ ; 2021C03050//Development Program of Zhejiang Province/ ; 82372109//National Natural Science Foundation of China/ ; },
abstract = {The treatment of Alzheimer's disease (AD) is severely hampered by the blood-brain barrier (BBB), which limits the delivery of therapeutic agents like donepezil (DPZ), an acetylcholinesterase inhibitor. While DPZ has multi-faceted benefits, its clinical efficacy is constrained by poor BBB penetration, requiring high doses that lead to significant side effects. To overcome this, we developed a brain-targeted nanotherapeutic utilizing apoferritin (AFn) nanoparticles loaded with DPZ (AFn-DPZ). We demonstrate that this platform, by binding to the EphB1 receptor on the blood-brain barrier, enables transient and reversible opening of the blood-brain barrier, thereby facilitating efficient and targeted drug delivery. Following intravenous administration in an AD mouse model, AFn-DPZ exhibited enhanced brain accumulation and sustained release of DPZ. This targeted delivery inhibited acetylcholinesterase activity, reduced amyloid plaque burden, alleviated neuroinflammation, attenuated oxidative damage, restored mitochondrial function, and upregulated the expression of brain-derived neurotrophic factor (BDNF). Consequently, AFn-DPZ treatment significantly improved cognitive performance compared to free DPZ. Our findings establish EphB1-mediated facilitation of BBB traversal as a promising strategy for enhancing nanotherapeutic delivery to the brain, offering a potent approach to address the complex pathology of AD.},
}

@article {pmid42406649,
year = {2026},
author = {Zawadzki, S and Okła, E and Michlewska, S and Bednarek, R and Ortega López, P and de la Mata, FJ and Jansons, J and Skrastina, D and Kreišmane, M and Piļipenko, V and Jansone, B and Ionov, M and Bryszewska, M and Miłowska, K},
title = {Tiered Evaluation of Carbosilane Dendrimer-siRNA Nanoplatform from Single-Cell Biocompatibility to Blood-Brain Barrier Model Dynamics and Murine Alzheimer Model Behavior Assessment.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.6c06099},
pmid = {42406649},
issn = {1944-8252},
abstract = {Blood-brain barrier (BBB) transport remains a primary constraint on achieving predictable central nervous system exposure for Alzheimer's disease (AD) therapeutics, motivating the evaluation of delivery platforms with barrier-resolved and functionally relevant end points. We assessed a carbosilane dendrimer (G3Si PEG6000) and its siRNA dendriplex using a tiered, upstream strategy spanning cell internalization, DNA damage screening, BBB model integrity and permeability, and in vivo AD-relevant murine model learning. At the cellular level, the dendrimer enhanced intracellular siRNA-associated signal with predominantly cytoplasmic localization, and siRNA complexation attenuated genotoxicity relative to the noncomplexed carrier. In a BBB triculture model, barrier function was preserved without sustained transendothelial electrical resistance (TEER) loss, and complementary tracer flux readouts showed time- and formulation-dependent, nonmonotonic changes, including TEER-permeability decoupling consistent with nonuniform perturbation and time-dependent changes in barrier-associated paracellular responses. In APOE4 knock-in mice, dendriplex treatment increased platform-zone crossings in the Morris Water Maze probe trial, whereas target-quadrant time showed only a modest, nonsignificant trend. Collectively, these integrated results indicate that siRNA complexation improves the BBB-relevant safety-performance balance of G3Si PEG6000 and supports further studies that directly link brain exposure and target engagement to cognitive outcomes.},
}

@article {pmid42410071,
year = {2026},
author = {Suo, X and Wan, P and Yu, J and Zhu, X and Tian, C and Li, S and Sun, G and Liu, H and Liu, S and Geng, M and Tian, J and Yang, W and Zhang, Y},
title = {The Protective Effects of Small-Molecule Compound 0242 Against LPS-Induced Neuroinflammation and in P301S Tau Transgenic Mice.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42410071},
issn = {1573-6903},
support = {2024CXPT029, 2025CXPT011//Key R&D Program of Shandong Province, China/ ; SYS202205//Shandong Laboratory Program/ ; ZR2024QH615//Shandong Provincial Natural Science Foundation/ ; },
mesh = {Animals ; Lipopolysaccharides/toxicity ; Mice, Transgenic ; *tau Proteins/genetics/metabolism ; Female ; *Neuroinflammatory Diseases/chemically induced/metabolism/drug therapy/prevention & control ; Mice ; Microglia/drug effects/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; Hippocampus/drug effects/metabolism ; Mice, Inbred C57BL ; },
abstract = {Neuroinflammation and tau pathology are central drivers of Alzheimer's disease (AD) progression, necessitating multi-target therapeutic strategies. Here, we evaluated the efficacy and mechanisms of 0242, a novel small-molecule derivative optimized from the berberine scaffold. In lipopolysaccharide (LPS)-stimulated BV-2 microglia, 0242 treatment significantly inhibited cell activation and nitric oxide release without cytotoxicity, while downregulating the mRNA levels of pro-inflammatory cytokines IL-1β and TNF-α. Transcriptomic profiling revealed that 0242 modulated LPS-induced inflammatory gene signatures by enriched core signaling cascades, including NF-κB, TLR, and JAK-STAT and upregulating cytoprotective genes such as ceruloplasmin (Cp) and Bcl2a1b. In vivo, oral administration of 0242 attenuated hippocampal astrocyte and microglial activation in an LPS-induced acute neuroinflammatory mouse model. Furthermore, in female P301S tau transgenic mice, 0242 treatment significantly improved spontaneous locomotor activity and recognition memory. Histological and biochemical analyses confirmed that 0242 suppressed hippocampal glial activation and reduced total tau protein levels in the prefrontal cortex. Collectively, these findings suggest that 0242 may exert potent anti-neuroinflammatory effects by modulating multiple immune signaling cascades and uniquely alleviates tau pathology in AD.},
}

Animals
Lipopolysaccharides/toxicity
Mice, Transgenic
*tau Proteins/genetics/metabolism
Female
*Neuroinflammatory Diseases/chemically induced/metabolism/drug therapy/prevention & control
Mice
Microglia/drug effects/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
Alzheimer Disease/drug therapy/metabolism
Hippocampus/drug effects/metabolism
Mice, Inbred C57BL

@article {pmid42410083,
year = {2026},
author = {Costello, H and Reeves, S and Glue, P and Young, AH and Howard, R},
title = {Depression in neurodegenerative disease: neurobiological mechanisms and emerging treatments.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42410083},
issn = {1476-5578},
abstract = {Depression is one of the most common and disabling neuropsychiatric complications of neurodegenerative diseases. In Alzheimer's disease (AD) and Parkinson's disease (PD), depressive syndromes affect more than one-third of patients and are associated with accelerated cognitive decline, reduced quality of life, and increased healthcare utilisation. Despite this burden, current antidepressant treatments show little or no efficacy in these populations, suggesting that depression arising in the context of neurodegeneration may reflect distinct underlying neurobiological mechanisms. Emerging evidence from molecular imaging, neuropathology, and cognitive neuroscience indicates disease-specific disruption of monoaminergic, glutamatergic, inflammatory, and reward-related circuits in AD and PD. These alterations may undermine the mechanisms of action of standard antidepressants and contribute to treatment resistance. Yet patients with cognitive impairment are routinely excluded from antidepressant trials, and few high-quality studies have evaluated novel therapies in neurodegenerative disease. In this narrative review, we synthesise current evidence on the neurobiological mechanisms underpinning depression in AD and PD and critically evaluate emerging pharmacological and neuromodulatory therapies targeting glutamatergic, serotonergic, dopaminergic, immune, and circuit-level dysfunction. Here, we highlight that depression in neurodegenerative disease offers a unique and underutilised model for mechanistically guided antidepressant development. We identify how interventions including glutamate modulators, dopaminergic agents, kappa opioid antagonists, immune-modulating therapies, and next-generation brain stimulation approaches may offer therapeutic promise. By aligning treatment development with disease-specific circuit and molecular pathology, this framework may improve outcomes for this neglected population while advancing precision psychiatry more broadly.},
}

@article {pmid42410183,
year = {2026},
author = {de Oliveira Portugal Couto, C and Hass das Eiras, ML and Juliao de Morais, JL and Leal Cordeiro Júnior, CW and Forlenza, OV and de Jesus Rodrigues de Paula, V},
title = {Chronic Lithium Exposure Reshapes PI3K-mTOR-linked Proteostatic Networks in the Hippocampus of an Alzheimer's Disease Mouse Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42410183},
issn = {1559-1182},
mesh = {Animals ; *Hippocampus/metabolism/drug effects/pathology ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Phosphatidylinositol 3-Kinases/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *TOR Serine-Threonine Kinases/metabolism ; *Lithium/pharmacology/administration & dosage/therapeutic use ; Signal Transduction/drug effects ; Protein Interaction Maps/drug effects ; Proteomics ; Mice ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β deposition, tau pathology, and alterations in signaling pathways involved in neuronal survival and protein homeostasis. Lithium has been suggested as a potential neuroprotective treatment, but the molecular mechanisms associated with its long-term effects are still not fully understood. In this study, we investigated the effects of chronic lithium treatment on hippocampal proteins associated with PI3K-related signaling in triple-transgenic Alzheimer's disease (3xTg-AD) mice. Wild-type and transgenic animals received either a lower or higher lithium dose for eight months. Hippocampal samples were analyzed by LC-MS/MS proteomics followed by protein interaction and functional enrichment analyses. From a total of 7768 identified proteins, bioinformatic analyses identified 157 proteins shared between APP-, MAPT-, and PI3K-associated datasets. Further network analyses identified 18 proteins related to PI3K signaling, including seven proteins shared among all three datasets: FKBP1A, HSPA1B, HSPA8, RAS-related proteins, RPL13, RPL19, and RPL24. These proteins are associated with protein folding, translation regulation, cellular stress responses, and signaling pathways. Chronic lithium treatment was associated with changes in the expression of these proteins in both wild-type and transgenic animals. The observed effects differed between the two lithium concentrations tested and did not follow a simple linear pattern. Our findings suggest that long-term lithium exposure is associated with changes in molecular networks related to proteostasis and translational regulation in the hippocampus. Although additional studies are needed to better understand the mechanisms involved, these results provide a proteomic framework for investigating lithium-sensitive pathways that may be relevant to Alzheimer's disease.},
}

Animals
*Hippocampus/metabolism/drug effects/pathology
*Alzheimer Disease/metabolism/drug therapy/pathology
*Phosphatidylinositol 3-Kinases/metabolism
Mice, Transgenic
Disease Models, Animal
*TOR Serine-Threonine Kinases/metabolism
*Lithium/pharmacology/administration & dosage/therapeutic use
Signal Transduction/drug effects
Protein Interaction Maps/drug effects
Proteomics
Mice

@article {pmid42395049,
year = {2026},
author = {Hofmann, A and Perneczky, R},
title = {Obstacles and solutions for implementing amyloid-targeting treatments in Europe.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70367},
pmid = {42395049},
issn = {2352-8729},
abstract = {Recent approvals of disease-modifying therapies by the European Medicines Agency mark a historic shift in the treatment landscape of Alzheimer's disease (AD) within the European Union that will challenge national health-care systems and require major adaptations and modernization. This Perspective article provides an overview of the major obstacles in Europe concerning successful implementation of amyloid-targeting treatments and offers potential solutions to overcome them. Major hurdles include a lack of recognition regarding the critical importance of an early, biomarker-based AD diagnosis; low acceptance of blood tests and digital cognitive screening tools; insufficient investment in magnetic resonance imaging capacities; and a fragmented infrastructure for clinical registries. We call on European clinicians, research institutions, and policy makers for a bold and coordinated action to urgently modernize diagnostic pathways and monitoring infrastructure to deliver novel AD treatments in a timely, safe, and equitable manner to all patients who may benefit.},
}

@article {pmid42395345,
year = {2026},
author = {Zhao, B and Zhou, R and Liu, P and Li, Q and Yan, Y and Du, J and Zhao, K and Liu, J and Wang, J and Qu, Q},
title = {FLOT1 and EEF1D: ac4C-related genes bridging Alzheimer's disease and sleep deprivation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1825164},
pmid = {42395345},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) and sleep deprivation (SD), two common conditions in the elderly, share complex molecular connections and may mutually influence each other's pathogenesis. Current drugs only relieve symptoms with limited efficacy, making it urgent to explore the shared pathological mechanisms and potential intervention targets of the two conditions. This study used bioinformatics: first screening AD-related genes associated with SD and N4-acetylcytidine (ac4C) from relevant data; then identifying key genes via Mendelian randomization (MR) analysis and machine learning; finally screening AD-related key cells with single-cell RNA sequencing (scRNA-seq) data, to provide a basis for revealing the molecular and cellular regulatory mechanisms of AD-SD comorbidity.

METHODS: This study integrated bulk RNA sequencing (RNA-Seq) and scRNA-seq data from the Gene Expression Omnibus (GEO) database to identify AD-related key genes associated with SD and ac4C. Machine learning algorithms, including MR, were applied to screen these key genes. Additionally, gene set enrichment analysis (GSEA) was conducted to explore the pathways associated with the key genes, while ssGSEA was used to assess differences in immune cell infiltration. For the scRNA-seq data, key cells involved in AD pathology were further identified. Subsequently, the differential expression of the two key genes was validated using peripheral blood samples collected from AD and SD patients.

RESULTS: Through MR analysis, machine learning algorithms, and other analytical approaches, FLOT1 and EEF1D were identified as key genes. GSEA revealed that these key genes were enriched in multiple pathways, including the lysosome pathway, chemokine signaling pathway, and leukocyte transendothelial migration. Immune cell infiltration analysis suggested that myeloid-derived suppressor cells (MDSCs) might serve as key immune cells. Additionally, scRNA-seq analysis identified microglia, CD4 + T cells, CD8 + T cells, and natural killer (NK) cells as key cell types involved in AD pathogenesis. Critically, these key genes were successfully validated in peripheral blood samples from AD and SD patients, aligning with the above analysis.

CONCLUSION: Overall, FLOT1 and EEF1D were identified as key genes associated with SD and ac4C in AD. This finding provided new grounds for the clinical diagnosis and treatment of AD.},
}

@article {pmid42395350,
year = {2026},
author = {Van Skike, CE and Hernandez, SF and Hussong, SA and Miller, LR and Makhlouf, H and Muppala, AC and DeRosa, N and Jahrling, JB and Dineley, KT and Galvan, V},
title = {mTOR drives cerebrovascular dysfunction and blood-brain barrier breakdown in a model of Alzheimer's disease with cerebral amyloid angiopathy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.23.733858},
pmid = {42395350},
issn = {2692-8205},
abstract = {Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid β fibrils (Aβ) within walls of the cerebrovasculature and contributes to intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in patients with Alzheimer's disease (AD) and in non-pathological aging. Previous studies have shown that mTOR drives cerebrovascular dysfunction and cognitive impairment observed in AD, vascular cognitive impairment, and normative aging. However, the mechanisms by which mTOR contributes to CAA are unknown. Here, we show that mTOR drives the accumulation of fibrillar vascular Aβ lesions in the Tg2576 Model of AD with CAA (using equal numbers of female and male mice), which directly impair endothelium-dependent cerebrovascular reactivity. Additionally, we found that blood-brain barrier (BBB) breakdown and remodeling of tight junction proteins, dependent on mTOR, are associated with increased cerebral microhemorrhages. Finally, we show that mTOR contributes to neurovascular uncoupling in Tg2576 AD mice through nNOS dysfunction and inhibition of non-nitric oxide synthase-dependent contributions to neurovascular coupling (NVC). Contextual memory impairments were ameliorated by the mTOR inhibitor rapamycin. Improvements in memory were associated with reduced cerebrovascular Aβ fibril accumulation, enhanced endothelium-dependent vasodilation, reduced fibrillar Aβ load, restoration of BBB integrity, attenuation of intracerebral microhemorrhage, and restoration of NVC. These data indicate that mTOR drives vascular accumulation of fibrillar Aβ, including those associated with brain vasculature, and mediates cerebrovascular dysfunction in a model of AD with CAA. Thus, mTOR inhibitors represent a promising treatment option for patients with CAA and AD.},
}

@article {pmid42395404,
year = {2026},
author = {Giorgio, J and Blazhenets, G and Landau, SM and Pezzoli, S and Yokoyama, JS and Soleimani-Meigooni, DN and Carrillo, MC and Grinberg, LT and Seeley, WW and Spina, S and Nudelman, KN and Apostolova, LG and Dickerson, BC and Jagust, WJ and Rabinovici, GD and Joie, R and , and , },
title = {Characterisation of Posterior Predominant Amyloid PET Binding Across Multiple Cohorts.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.17.733031},
pmid = {42395404},
issn = {2692-8205},
abstract = {The standard approach to quantify amyloid (Aβ) PET averages uptake within a single cortical mask that assumes no clinically relevant spatial heterogeneity in uptake patterns. Here, in a sample of 12,379 clinically impaired participants taken from four phenotypically diverse cohorts we use data-driven approaches to discover heterogeneous patterns of Aβ-PET binding, uncovering a reproducible and clinically relevant pattern of posterior predominant Aβ-PET binding. In particular, Aβ-PET positive participants who have posterior predominant binding are less likely to be APOE -ε4 carriers, more severely impaired, have thinner cortex in posterior regions, and greater posterior tau PET burden. Furthermore, in a subsample of participants with neuropathological assessment, participants with posterior predominant Aβ binding have a higher likelihood of having cerebral amyloid angiopathy at autopsy. These findings suggest that Aβ-PET accumulates along two orthogonal axes with biological and clinical relevance, indicating that the standard approach to assess Aβ-PET is insufficient to capture meaningful signal from Aβ-PET imaging. This work has implications for the diagnosis and treatment of Alzheimer's disease and extends our understanding of the mechanisms governing variable Aβ-PET distribution and its downstream effects.},
}

@article {pmid42395537,
year = {2024},
author = {Wang, R and Maloney, B and Nho, K and Beck, J and Counts, SE and Lahiri, DK},
title = {Human microRNA-153-3p targets specific neuronal genes and is associated with the risk of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.09.07.611728},
pmid = {42395537},
issn = {2692-8205},
abstract = {Alzheimers disease (AD) is a progressive degenerative disease characterized by a significant loss of neurons and synapses in cognitive brain regions and is the leading cause of dementia worldwide. AD pathology comprises extracellular amyloid plaques and intracellular neurofibrillary tangles. However, the triggers of this pathology are still poorly understood. Repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF), a transcription repressor of neuronal genes, is dysregulated during AD pathogenesis. How REST is dysregulated is still poorly understood, especially at the post-transcriptional level. MicroRNAs (miRNAs), a group of short non-coding RNAs, typically regulate protein expression by interacting with target mRNA transcript 3-untranslated region (UTR) and play essential roles in AD pathogenesis. Herein, we demonstrate that miR-153-3p reduces REST 3-UTR activities, mRNA, and protein levels in human cell lines, along with downregulating amyloid β precursor protein (APP) and α-synuclein (SNCA). We determine by mutational analyses that miR-153-3p interacts with specific targets via the seed sequence present within the respective mRNA 3-UTR. We show that miR-153-3p treatment alters the expression of these specific proteins in human neuronally differentiated cells and human induced pluripotent stem cells and that miR-153-3p is itself dysregulated in AD. We further find that single nucleotide polymorphisms (SNPs) within 5kb of the MIR153-1 and MIR153-2 genes are associated with AD-related endophenotypes. Elevation of miR-153-3p is associated with reduced AD probability, while elevated REST may associate with a greater AD probability. Our work suggests that a supplement of miR-153-3p would reduce levels of toxic protein aggregates by reducing APP, SNCA, and REST expression, all pointing towards a therapeutic and biomarker potential of miR-153-3p in AD and related dementias.},
}

@article {pmid42396326,
year = {2026},
author = {Ferreira-Atuesta, C and Schubert, KM and Noain, D and Draganski, B and Galovic, M and , },
title = {Association of antiseizure medication with lower amyloid and tau burden.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.22.26356204},
pmid = {42396326},
abstract = {Network hyperexcitability is increasingly implicated in prodromal Alzheimer's disease and may be suppressed by antiseizure medications (ASMs). ASMs are widely prescribed to older adults, yet whether their use relates to Alzheimer's-disease biomarkers at the population level is unknown. In 52,537 participants in the National Alzheimer's Coordinating Center (NACC) study, we compared cerebrospinal-fluid biomarkers, amyloid and tau positron emission tomography (PET) between ASM users and non-users using inverse-probability-of-treatment weighting with gradient-boosted propensity scores. ASM users showed directionally lower amyloid across multiple brain regions, amplifying markedly in APOE ε4 carriers (Centiloid β = -25.7, p = 0.007). All three temporal tau-PET composites were significantly lower in users (META-temporal β = -0.05, p = 0.01). The amyloid finding replicated independently in the the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (Centiloid β = -8.6, p = 0.01), whereas four comparator drug classes showed no amyloid signal. These convergent observational findings provide a quantitative framework for evaluating ASMs as candidate disease-modifying agents in Alzheimer's disease.},
}

@article {pmid42398193,
year = {2026},
author = {Saumur, TM and Ashraf, H and Mathers, KE and Wagner, B},
title = {Pharmacotherapy for Alzheimer's Disease and Dementias in Long-Term Care: A Real-World EHR Study.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {9},
pages = {106293},
doi = {10.1016/j.jamda.2026.106293},
pmid = {42398193},
issn = {1538-9375},
abstract = {OBJECTIVES: To characterize contemporary pharmacologic medication order patterns for Alzheimer's disease (AD) and related dementias (ADRD) among US long-term care (LTC) residents and to examine facility- and resident-level factors associated with treatment.

DESIGN: Retrospective and observational study.

SETTING AND PARTICIPANTS: Electronic health record data from 1,675,873 LTC residents in the PointClickCare Life Sciences clinical database included 295,946 with a documented ADRD diagnosis in skilled nursing facilities in the United States who remained in facility at the end of the study window (January-April 2025).

METHODS: Residents were classified as treated/untreated based on the presence of ≥1 ADRD medication order as outlined by the Alzheimer's Association. Analyses incorporated demographics, comorbidities, medication burden, and facility characteristics. Multivariate logistic regression estimated the odds of having an ADRD medication order.

RESULTS: Overall, 82.0% of residents with ADRD had ≥1 order for ADRD medication. Treatment was most common among residents with Lewy body dementia (91.1%) and early onset AD (90.3%) and least frequent among Asian (72.3%), Native Hawaiian, or Other Pacific Islander (74.6%) and short-stay residents (75.6%). Treated residents exhibited a higher medication burden (mean, 8.6 vs 6.3). Diagnoses for other chronic conditions as well as specific ADRD subtypes strongly impacted probability of treatment; diabetes was associated with lower odds of treatment, whereas ADRD subtypes strongly predicted treatment.

CONCLUSIONS AND IMPLICATIONS: Approximately one-fifth of residents with ADRD did not have an ADRD medication order, and treatment varied significantly by nonclinical predictors. These findings underscore the need to investigate and understand possible treatment disparities, optimize polypharmacy management, and discover new ADRD treatments, and develop safer and more effective ADRD therapies.},
}

@article {pmid42398685,
year = {2026},
author = {Tang, Y and Huang, L and Li, W and Gao, T and Shi, N and Zhu, Y and Wang, Y and Nan, J and Zhu, Y and Li, J and Ma, Y},
title = {Efficacy of Non-Invasive Brain Stimulation in Alzheimer's Disease: An Umbrella Review of Meta-Analyses.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106844},
doi = {10.1016/j.neubiorev.2026.106844},
pmid = {42398685},
issn = {1873-7528},
abstract = {This umbrella review integrates systematic reviews and meta-analyses to evaluate the efficacy of non-invasive brain stimulation (NIBS) in Alzheimer's disease (AD). We searched seven databases from inception to 20 June 2025 for relevant literature. Effect sizes and 95% confidence intervals were extracted using a structured approach and visualized through effect size heatmaps and evidence mapping. Methodological quality and evidence certainty were assessed using AMSTAR 2 and GRADE, respectively. A total of 42 publications, encompassing 130 primary studies and 5,771 patients, were included. NIBS yielded significant immediate improvements in global cognition, daily living, neuropsychiatric symptoms, memory, language, executive function, global impression, visuospatial function, and cholinergic transmission. Among 119 outcome associations, 57.1% were statistically significant (p < 0.05). Long-term benefits were sustained only in global cognition. Moreover, these techniques exhibited modality-specific effects on cognitive and clinical outcomes. Subgroup analysis identified repetitive transcranial magnetic stimulation (rTMS) as the most effective technique, supported by 16 moderate- to high-quality associations. Transcranial direct current stimulation (tDCS) showed inconsistent results with only three moderate-quality associations, while transcranial alternating current stimulation (tACS) demonstrated potential but limited evidence. Intermittent theta burst stimulation (iTBS) showed no significant cognitive benefits in the limited available evidence. Available safety evidence, though limited, suggests generally mild and transient adverse effects. NIBS, particularly rTMS, shows therapeutic potential for AD, though this is based on preliminary evidence. Future multicenter long-term studies and standardized protocols are needed to facilitate the precise application of NIBS in AD treatment.},
}

@article {pmid42399403,
year = {2026},
author = {Endrizzi, W and Ragni, F and Bovo, S and Chandra, A and Moroni, M and Jurman, G and Osmani, V},
title = {The landscape of artificial intelligence in neurodegenerative diseases: a systematic review.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01669-5},
pmid = {42399403},
issn = {2730-664X},
abstract = {BACKGROUND: The rising global burden of neurodegenerative diseases underscores an urgent need for advanced research in diagnosis, prognosis, and treatment. Artificial Intelligence (AI) methods, particularly when applied to multimodal data, offer a powerful tool to address these challenges. However, a comprehensive overview and critique of the current landscape of AI methods is lacking.

METHODS: 4,685 records of peer-reviewed, primary research articles were screened and 1,956 articles reviewed in full text, yielding 1,186 included studies. For each included study, clinical objectives, disease focus, data modalities, modelling approach, evaluation strategy, and reporting practices were extracted.

RESULTS: Fewer than 5% of studies integrated pharmacological treatments into their predictive models, limiting the extent to which models can directly inform clinical decision-making. Neuroimaging was the predominant input modality, while integration of other clinically relevant data types was relatively rare. Reproducibility rates remain critically low at 35%, and external validation practices fail to use geographically and demographically diverse datasets.

CONCLUSIONS: Overall, AI research in neurodegenerative diseases suffers from significant limitations in reproducibility, data inclusivity, and clinical translatability. We provide a set of recommendations that can be adopted to address these issues and improve reliability and downstream clinical utility.},
}

@article {pmid42401549,
year = {2026},
author = {Liu, C and Zhang, T and E, ED and Xu, TY and Yang, FR and Li, JW and Shang, Q and Zhang, ZY and Shen, HW and Zhang, XQ},
title = {Maraviroc attenuates inflammation-exacerbated cognitive and amyloid pathology in an early-stage Alzheimer's disease mouse model.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04215-y},
pmid = {42401549},
issn = {2158-3188},
support = {32201322//National Natural Science Foundation of China (National Science Foundation of China)/ ; LY24H090001//Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)/ ; },
abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive decline, and increasing evidence indicates that systemic inflammation can accelerate disease progression. Maraviroc, a CCR5 antagonist approved for the treatment of human immunodeficiency virus (HIV) infection, has shown neuroprotective effects in several neurological contexts, but its role in AD-related pathology remains unclear. In this study, cognitive performance was assessed in 5 × FAD mice using the Y-maze, novel object recognition, novel location recognition, and social discrimination tests. Amyloid-related changes were evaluated by hippocampal APP/Aβ immunoblotting and plaque staining using 6E10 and Thioflavin S. Glial responses were examined by IBA1 and GFAP immunostaining, and inflammatory cytokines were quantified by ELISA. We found that 5 × FAD mice exhibited age-dependent cognitive impairments, with detectable deficits emerging at 3 months of age. Systemic administration of lipopolysaccharide (LPS) further exacerbated cognitive dysfunction, amyloid-related alterations, and neuroinflammatory responses in young 5 × FAD mice. Maraviroc treatment attenuated LPS-associated cognitive impairments, reduced amyloid-related measures, and dampened pro-inflammatory cytokine responses, with a trend toward reduced microglial cell density. Collectively, these findings demonstrate that systemic inflammation accelerates Alzheimer's-like pathology and cognitive decline, and suggest that pharmacological modulation of neuroinflammatory signaling by maraviroc may mitigate inflammation-driven disease exacerbation at early stages.Schematic diagram illustrating the effects of maraviroc on LPS-induced cognitive deficits in 3-month-old 5 × FAD mice. In this model, maraviroc is associated with modulation of glial inflammatory responses, reduced pro-inflammatory cytokine levels, and alleviation of amyloid pathology in the hippocampus, which together coincide with improved cognitive performance. Figure created with BioRender.com.},
}

@article {pmid42402307,
year = {2026},
author = {Chen, Z and Yang, K and Lin, F and Tang, W and Shi, Y and Zhou, S and Liu, J and You, Y},
title = {White matter abnormalities in Alzheimer's disease: Implications for pathophysiology, diagnosis, and treatment.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103229},
doi = {10.1016/j.arr.2026.103229},
pmid = {42402307},
issn = {1872-9649},
abstract = {White matter (WM) abnormalities have emerged as a critical element in Alzheimer's disease (AD) pathogenesis, shifting from their former status as a passive consequence to an active contributor to disease progression. Notably, microstructural WM alterations, detectable early via advanced neuroimaging techniques such as diffusion tensor imaging, frequently precede overt gray matter atrophy and cognitive decline, highlighting their potential as early contributors to AD pathogenesis. The origins of WM pathology are multifactorial, involving a complex interplay among β-amyloid (Aβ) and tau aggregation, energy dysmetabolism, neuroinflammation, vascular dysfunction, and cellular senescence. Importantly, we emphasize a paradigm-shifting perspective: WM degeneration acts not merely as a downstream outcome but as a key driver of AD pathogenesis, capable of accelerating protein aggregation, amplifying neuroinflammation, and compromising neural plasticity. Given its early manifestation and close association with symptom onset, WM integrity has emerged as a sensitive and reliable biomarker for early AD detection and progression monitoring. Moving beyond diagnostics, the growing understanding of WM pathophysiology has unveiled a new frontier of therapeutic interventions aimed at myelin regeneration and WM protection. Despite persisting translational challenges, targeting WM integrity represents a pivotal avenue for developing disease-modifying therapies capable of slowing disease progression and improving clinical outcomes in patients with AD.},
}

@article {pmid42402880,
year = {2026},
author = {, },
title = {[Standard operating procedure for pre-analytical blood biomarker processing in Alzheimer's disease (2026 edition)].},
journal = {Zhonghua yi xue za zhi},
volume = {106},
number = {25},
pages = {2568-2578},
doi = {10.3760/cma.j.cn112137-20260202-00363},
pmid = {42402880},
issn = {0376-2491},
support = {2023YFC3605400//National Key Research and Development Program of China/ ; 82588301//Natural Science Foundation of China/ ; 2024GGXM003//Joint Project of the Chongqing Science and Technology Bureau and the Health Commission/ ; },
mesh = {*Alzheimer Disease/blood/diagnosis ; Humans ; *Biomarkers/blood ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; },
abstract = {Alzheimer's disease (AD) is a major health threat to the elderly. With the clinical application of disease-modifying therapeutic drugs, early and accurate diagnosis of AD has become increasingly essential. Given the ease of collection, blood biomarker detection has emerged as a crucial method for early screening, clinical diagnosis, and disease monitoring of AD. In recent years, substantial progress has been achieved in the research of AD blood biomarkers, and some indicators have been introduced into clinical practice. However, the detection of AD blood biomarkers, such as β-amyloid protein and phosphorylated tau protein, are highly susceptible to pre-analysis factors, which reduces the reliability of their clinical application and restricts the comparability among different blood biomarker studies. Currently, in China, there is a growing trend in the scientific research, testing product development, and clinical application of AD blood biomarkers. Therefore, it is necessary to standardize the AD blood biomarker detection in China. Based on this background, Cognitive Impairment Working Group of the National Medical Quality Control Center for Neurological Diseases established the "Standard operating procedure for pre-analytical blood biomarker processing in Alzheimer's disease (2026 edition)". This standard is developed in line with international recommendations, incorporating the practical experience of blood biomarker research in China and taking into consideration both clinical and research needs. It formulates a standardized operating procedure for the pre-treatment of blood samples, providing a quality control reference for the research and clinical application of AD blood biomarkers in China.},
}

*Alzheimer Disease/blood/diagnosis
Humans
*Biomarkers/blood
Amyloid beta-Peptides/blood
tau Proteins/blood

@article {pmid42394935,
year = {2026},
author = {Leone, L and Kiernan, TJ and Kuwabara, S and Barnett, M and Devenney, E and Ahmed, RM and Lin, CS},
title = {A convergence of global epidemics: diabetes as a modulator of neurodegenerative and neuro-inflammatory disorders.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1824840},
pmid = {42394935},
issn = {1664-2295},
abstract = {Diabetes mellitus (DM) and neurological disorders are rapidly converging global health burdens, driven by population ageing, the growing prevalence of metabolic syndrome, and limited early detection and disease-modifying therapies for many neurological syndromes. Beyond its established role in diabetes-related peripheral neuropathy, DM is increasingly implicated as a modifier of risk, phenotype, and prognosis across a wide range of central and peripheral nervous system diseases. In this narrative review, we synthesize current epidemiological, clinical, genetic, and mechanistic evidence examining the relationship between DM and 10 clinically important neurological disorders: Alzheimer's disease (AD), vascular dementia (VaD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multiple sclerosis (MS), myasthenia gravis (MG), and neuromyelitis optica spectrum disorder (NMOSD). Across these conditions, DM acts as a context-dependent disease modifier, increasing risk in some disorders, appearing protective or delaying onset in others, and influencing disease phenotype, progression, and treatment response. We highlight potential areas of mechanistic convergence, such as insulin resistance, inflammation, disrupted energy homeostasis, and genetic predisposition, alongside important divergences shaped by disease-specific pathology. We also discuss the clinical and translational implications of this interface, including diagnostic challenges, opportunities for improved risk stratification, and growing interest in repurposing antidiabetic therapies, particularly metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, for neurological benefit. As the global burden of diabetes and neurological disease escalates, it is crucial to better understand the interplay between metabolic dysfunction, neurodegeneration, and neuro-immune pathways. The integration of insights across diseases may inform prevention strategies and support the development of therapeutic interventions at the metabolic-neurological interface.},
}

@article {pmid42394931,
year = {2026},
author = {Jeon, YH and Kim, JA and Kang, DY and Lee, S and Choi, NK and Park, JY},
title = {Ginkgo biloba extract for dizziness-related symptoms in central neurological disorders: a systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1860538},
pmid = {42394931},
issn = {1664-2295},
abstract = {BACKGROUND AND PURPOSE: Dizziness associated with central neurological disorders-broadly defined as dizziness or vertigo attributable to central nervous system pathology affecting central vestibular processing-is a clinically challenging and heterogeneous condition with limited treatment options. Ginkgo biloba extract-through its microcirculatory, neuroprotective, and anti-inflammatory mechanisms-represents a biologically plausible intervention. However, its efficacy in this setting has not been comprehensively established. We evaluated the efficacy and safety of Ginkgo biloba extract through a systematic review and meta-analysis of randomized controlled trials (RCTs).

METHODS: Nine international and Korean databases were searched from January 1974 through November 2025. Studies were eligible if they were RCTs enrolling adults aged 18 years or older with cerebrovascular disease, neurodegenerative disease, or central vestibular dysfunction who had dizziness, vertigo, or balance-related symptoms or relevant outcome assessments. Cochrane RoB 2.0 tool and certainty of evidence was rated using the Assessment, Development and Evaluations (GRADE) approach. Prespecified subgroup analyses by underlying etiology and intervention type, together with leave-one-out sensitivity analyses, were performed to explore heterogeneity.

RESULTS: Nine RCTs (N = 2,394) were included; participants were predominantly drawn from dementia populations (71.6%), with smaller contributions from cerebral arteriosclerosis (23.0%) and vertebrobasilar or posterior circulation disorders (5.4%). Ginkgo biloba significantly reduced dizziness/vertigo severity on the 11-point box scale (MD - 0.76, 95% CI - 1.35 to -0.18; p = 0.01) and VAS (SMD - 0.38, 95% CI - 0.58 to -0.19; p = 0.0001). Moderate-certainty evidence suggested improvements in functional outcomes and quality of life, including the Alzheimer's Disease Activities of Daily Living International Scale (MD = -0.17, 95% CI: -0.22 to -0.13) and the Dementia Quality of Life - Proxy (MD = 2.00, 95% CI: 0.85 to 3.15). The intervention was generally well tolerated, with significantly lower risks of angina pectoris (OR 0.51, 95% CI 0.31 to 0.85) and tinnitus (OR 0.37, 95% CI 0.22 to 0.63) and no significant increase in other adverse events.

CONCLUSION: Ginkgo biloba extract may reduce dizziness severity and improve daily functioning in patients with central neurological disorders accompanied by dizziness or vertigo, with a favorable safety profile. However, given the small number of eligible trials, substantial clinical and statistical heterogeneity, and the predominance of dementia-derived data, these findings should be interpreted with caution. Well-designed RCTs in clearly defined central vestibular populations, ideally confirmed by neuroimaging or vestibular testing, are needed to confirm these results.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420251229692, PROSPERO: CRD420251229692.},
}

@article {pmid42390710,
year = {2026},
author = {Medeiros, EB and de Oliveira Monteiro, I and Kluwe-Schiavon, B and Possamai, OL and Fenilli, GP and Keller, GS and Lidio, AV and Casagrande, DD and Souza, CSM and de Bem Silveira, G and de Almeida, RCS and Vicente, HB and Magenis, ML and Luiz, GP and Damiani, AP and de Andrade, VM and Budni, J},
title = {Effect of Probiotic Supplementation in Older Individuals with Mild Cognitive Impairment and Alzheimer's Disease: A Randomized, Placebo-Controlled, Triple-Blind Clinical Trial.},
journal = {Probiotics and antimicrobial proteins},
volume = {},
number = {},
pages = {},
pmid = {42390710},
issn = {1867-1314},
abstract = {Alzheimer's disease (AD) is the most common type of dementia in older adults and often precedes mild cognitive impairment (MCI). These conditions are associated with biological alterations involving chronic inflammation, neuronal dysfunction, and genomic instability. In parallel, growing evidence has suggested a role for the gut-brain axis in cognitive aging, and probiotics have been investigated as a potential strategy to modulate inflammatory and neurotrophic pathways. This randomized, triple-blind, placebo-controlled clinical trial evaluated the effects of 12 weeks of supplementation with a probiotic blend containing Lactobacillus and Bifidobacterium strains in older adults classified as cognitively unimpaired (CU), MCI, or AD. The study examined DNA damage, inflammatory cytokines, neurotrophic factors, and stool consistency before and after the intervention. Overall, probiotic supplementation showed limited and heterogeneous effects across outcomes. DNA damage analyses did not indicate increased alkaline or oxidative DNA damage after probiotic supplementation, supporting the absence of detectable genotoxicity over the intervention period. Changes in inflammatory and neurotrophic biomarkers were more strongly related to time and diagnostic subgroups than to treatment allocation. Exploratory findings suggested a possible subgroup-specific effect on neurotrophic markers, particularly an increase in NGF in the MCI probiotic arm, but this pattern was not consistent across the broader biomarker panel. Stool consistency did not show reliable pre- to post-intervention changes. These findings suggest that the probiotic formulation was safe from a genotoxic perspective but did not produce a generalized biological effect across inflammatory, neurotrophic, or gastrointestinal outcomes. Larger studies incorporating dietary monitoring and microbiota profiling are needed to clarify whether specific probiotic strains can influence biological pathways relevant to cognitive aging.},
}

@article {pmid42391577,
year = {2026},
author = {Bautista, JR and Goth, O and Anbari, AB and Powell, KR},
title = {Readability and Linguistic Characteristics of Alzheimer's Disease and Related Dementias Prevention, Symptom, and Treatment Information from Generative Artificial Intelligence Chatbots.},
journal = {Journal of gerontological nursing},
volume = {52},
number = {7},
pages = {7-11},
doi = {10.3928/00989134-20260608-03},
pmid = {42391577},
issn = {0098-9134},
mesh = {Humans ; *Alzheimer Disease/prevention & control/therapy ; Generative Artificial Intelligence ; *Comprehension ; *Linguistics ; *Dementia/prevention & control/therapy ; },
abstract = {PURPOSE: To examine the readability and linguistic characteristics of Alzheimer's disease and related dementias (ADRD) prevention, symptom, and treatment information from generative artificial intelligence (GenAI) chatbots.

METHOD: We analyzed 66 outputs from free-to-use GenAI chatbots. We extracted readability (word count, Fleisch Reading Ease, and Fleisch-Kincaid Grade Level) and linguistic scores (analytical thinking, clout, authenticity, and emotional tone) using Microsoft Word and the Linguistic Inquiry and Word Count software. Data were analyzed using descriptive statistics, t tests, analysis of variance, and multivariate analysis of variance.

RESULTS: ADRD information from GenAI chatbots, especially treatment information, had college-level readability. Linguistic analyses indicate a high analytical thinking score and low scores for clout, authenticity, and emotional tone.

CONCLUSION: Our sample of ADRD GenAI information exceeded recommended reading levels for patient education materials. Although the outputs exhibited logical thinking, they also included uncertain, inauthentic, and negative tones. ADRD caregivers should be aware of these characteristics when using GenAI chatbots for ADRD information-seeking.},
}

Humans
*Alzheimer Disease/prevention & control/therapy
Generative Artificial Intelligence
*Comprehension
*Linguistics
*Dementia/prevention & control/therapy

@article {pmid42391744,
year = {2026},
author = {Xin, Y and Sheng, J and Wang, L},
title = {A review of Alzheimer's disease diagnosis and prognosis models based on multimodal deep learning.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {42391744},
issn = {2191-0200},
abstract = {Although some drugs have been approved for clinical treatment, early diagnosis and intervention remain the most effective strategies for managing Alzheimer's disease (AD) at present. With advances in deep learning and multimodal fusion, an increasing number of complex frameworks have been proposed. This paper systematically reviews multimodal deep learning-based models for AD diagnosis between 2020 and 2026. Beyond the technical survey, we explore how to deal with the heterogeneous modality integration and missing modality processing. From these experimental results, many models show impressive performance on public datasets. However, we have noticed a troubling problem that these "lab-perfect" results often falter when they face the chaos of the real-world. Because of the persistent black-box problem and the hidden traps of data leakage, the path to clinical use is still uphill. This work suggests that it is time to move beyond chasing tiny gains in accuracy and focus on building models that doctors can truly trust, understand, and use in real clinical settings.},
}

@article {pmid42391923,
year = {2026},
author = {Guo, H and Zheng, S and Shi, X and Wang, X and Ma, R and Li, G},
title = {VER155008 rescues cognitive impairment in P301S tauopathy mice by promoting HSPA8-mediated lipophagy.},
journal = {European journal of pharmacology},
volume = {1030},
number = {},
pages = {179107},
doi = {10.1016/j.ejphar.2026.179107},
pmid = {42391923},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) features tau accumulation and pathogenic lipid droplet (LD) buildup, driving neurodegeneration through oxidative stress and neuroinflammation. The chaperone heat shock protein family A member 8 (HSPA8) is upregulated in AD, which may have implications for impaired LD clearance via lipophagy. We investigated whether targeting HSPA8 with the small-molecule antagonist VER155008 alleviates tau pathology and cognitive deficits by activating lipophagy in P301S tauopathy models. P301S tau transgenic mice and HEK293T-P301S cells were utilized. Western blotting, immunohistochemistry, and immunofluorescence were performed to assess HSPA8 levels, lipophagy, tau proteins, and inflammatory markers. VER155008 or vehicle control was administered to P301S mice for four weeks, starting at seven months of age. Cognitive function was evaluated using the Morris water maze and novel object recognition tests. Synaptic density was assessed through Golgi staining and electron microscopy. HSPA8 was elevated in P301S mice, correlating with impaired lipophagy and suppressed AMP-activated protein kinase (AMPK) activity. VER155008 treatment restored cognitive function and synaptic density. Critically, it activated lipophagy and reduced hippocampal LDs and tau pathology. Moreover, HSPA8 overexpression suppressed lipophagy and increased both LD accumulation and tau pathology. Inhibition of HSPA8 by VER155008 activates AMPK-mediated lipophagy, concurrently reducing tau pathology, oxidative stress, and neuroinflammation in AD models. These beneficial effects were eliminated by treatment with the AMPK inhibitor Compound C. This identifies the HSPA8-lipophagy axis as a promising therapeutic target for tauopathies.},
}

@article {pmid42391929,
year = {2026},
author = {Wang, Y and Sang, J and Li, H and Ren, X and Chen, C and Zheng, N and Xiao, H and Wei, Y and Xu, L and Jiang, R and Zhang, W and Xu, Z and Ge, L and Zhu, J and Xiong, B and Chen, Y and Feng, F and Sun, H},
title = {Development of potent BChE/Nrf2 modulators for Alzheimer's disease treatment via dual suppression of ferroptosis.},
journal = {European journal of medicinal chemistry},
volume = {317},
number = {},
pages = {119093},
doi = {10.1016/j.ejmech.2026.119093},
pmid = {42391929},
issn = {1768-3254},
abstract = {Targeting multiple pathological mechanisms holds significant potential for Alzheimer's disease (AD) therapy. Here, we designed 50 hybrids combining the benzimidazole-aminofurazan scaffold of a BChE inhibitor (S06-1064) with the 1,2,4-oxadiazole moiety of an Nrf2 activator (6). After four optimization rounds, S27-1046 and S27-1047 emerged as potent, selective BChE inhibitors and Nrf2 activators (S27-1046: eqBChE IC50 = 2.51 ± 1.51 nM, hBChE IC50 = 128.30 ± 16.89 nM, FP IC50 = 188.20 ± 57.11 nM, 4.73-fold ARE induced fold at 20 μM; S27-1047: eqBChE IC50 = 7.16 ± 2.96 nM, hBChE IC50 = 296.10 ± 55.78 nM, FP IC50 = 36.87 ± 23.07 nM, 7.42-fold ARE induced fold at 20 μM). They directly bind Keap1, disrupt Keap1-Nrf2 interaction, enhance antioxidant enzyme expression, and activate the GSH-GPX4 axis to inhibit Aβ-induced ferroptosis. Both compounds also protect against oxidative stress and neuroinflammation. S27-1047 showed superior Nrf2 activation and Keap1 binding, thus was selected for in vivo evaluation. In an Aβ-induced AD mouse model, S27-1047 significantly improved cognition, outperforming mono- or combination therapies. It has 12.62% oral bioavailability and crosses the BBB. This work presents multi-target agents targeting BChE, Nrf2, and ferroptosis for effective AD therapy.},
}

@article {pmid42391971,
year = {2026},
author = {Ning, Y and Chen, M and Yang, H and Jia, J},
title = {Sotagliflozin improves cognitive deficits and attenuates neuroinflammation of Alzheimer's disease.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {4},
pages = {e00946},
doi = {10.1016/j.neurot.2026.e00946},
pmid = {42391971},
issn = {1878-7479},
abstract = {Effective treatments for Alzheimer's disease (AD) are limited. Due to shared pathological mechanisms between AD and diabetes, antidiabetic drugs like sodium-glucose cotransporter-2 inhibitors (SGLT2is) are potential therapeutic options. Although SGLT2is have shown cognitive benefits in diabetes models, their effects in AD models are not fully established. This study aimed to evaluate the therapeutic effects of sotagliflozin (Sota), an SGLT2i, in both in vivo and in vitro AD models. The network pharmacology analysis was used to predict the potential targets and pathways of Sota. And we selected 6-month-old APP/PS1 transgenic mice to investigate the effects of Sota. Cognitive function was assessed using the Morris water maze test. Immunohistochemistry and immunofluorescence were employed to quantify amyloid-beta (Aβ) plaque deposition in the hippocampal or cortex and analyze neuronal loss. Additionally, amyloid β oligomers induction and microglial cells were used to evaluate the effects of Sota on the release of pro-inflammatory mediators and to investigate the underlying mechanisms. In vivo, Sota treatment improved cognitive impairments, reduced pro-inflammatory cytokines, inhibited microglial activation, and promoted neuronal survival. In vitro, Sota mitigated Aß oligomer-induced toxicity in microglial cells by decreasing reactive oxygen species and pro-inflammatory cytokine release. Mechanistically, Sota treatment was associated with suppression of extracellular signal-regulated kinase (ERK) signaling. Our findings suggest that Sota improved cognitive impairment and attenuates neuroinflammation in AD. Sota may be a promising candidate for the treatment of AD.},
}

@article {pmid42392137,
year = {2026},
author = {Chen, Y and Yan, F and Xiao, P and Li, X and Yu, L and Dong, S and Yao, C},
title = {Non-invasive nanosecond transcranial pulsed electric fields: a deep-penetrating, high-field stimulation that suppresses hippocampal β-amyloid and improves cognitive deficits in Alzheimer's disease model.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/ae8579},
pmid = {42392137},
issn = {1741-2552},
abstract = {OBJECTIVE: Hippocampal β-amyloid (Aβ) pathology may induce early circuit dysfunction and memory impairment in Alzheimer's disease (AD), making it a key target for slowing disease progression. However, existing transcranial electrical stimulation approaches, while remaining within safety limits, are insufficient to non-invasively generate sufficiently strong electric fields in deep brain regions. Here, we investigated whether nanosecond transcranial pulsed electric field stimulation (ns-tPFS) could provide a non-invasive deep-target strategy for modulating hippocampal Aβ pathology in an AD model.

APPROACH: The 10-month-old 5xFAD mice were selected for delivering repeated ns-tPFS (500 ns, 500 V, 1 Hz). The intracranial electric field exposure was estimated using finite-element modeling (FEM). Treatment effects were evaluated using the Morris water maze, Y-maze, immunofluorescence of Aβ deposition in the hippocampus and cortex, and western blotting of Aβ-related proteins. In addition, the structural responses of Aβ oligomers to pulsed electric fields were examined by employing molecular dynamics simulations, and structural brain safety was assessed by 9.4 T small-animal MRI.

MAIN RESULTS: ns-tPFS generated transient hippocampal electric fields on the order of 104 V/m. It reduced the hippocampal Aβ burden and was associated with coordinated changes in Aβ-related pathways, including decreased amyloidogenic processing and modulated Aβ transport-related receptors. Molecular dynamics simulations further suggested that Aβ oligomers are structurally sensitive to nanosecond-scale electric field transients within the hippocampal field range estimated by FEM. These changes were accompanied by improved spatial and working memory in 5xFAD mice. In contrast, under the present stimulation regimen, healthy mice were observed with no detectable cognitive impairment, or macroscopic MRI abnormalities.

SIGNIFICANCE: ns-tPFS may be a promising non-invasive deep-target electric-field strategy for mitigating hippocampal Aβ pathology and improving cognitive performance in an AD mouse model.},
}

@article {pmid42392515,
year = {2026},
author = {Pandey, JK and Verma, SK and Kumar, J and Perwej, Y and Jha, DSK and Panchal, BY and Ferdouse, R and V, S and Banerjee, S and Tiwari, M and Badal, R and Mandal, P and Baghel, JS},
title = {Transformative Role of Advanced Neural Computation in Clinical Image Diagnostics: A Review of Key Concepts and Applications.},
journal = {Seminars in ultrasound, CT, and MR},
volume = {},
number = {},
pages = {},
doi = {10.1053/j.sult.2026.06.010},
pmid = {42392515},
issn = {1558-5034},
abstract = {Medical imaging plays a crucial role in modern diagnostic practices, but traditional techniques often face limitations in accuracy, efficiency, and scalability. The emergence of deep learning (DL) has led to significant improvements that are transforming this field. This review discusses how DL algorithms are enhancing diagnostic imaging by improving accuracy, enabling automated analysis, and supporting personalized treatment plans. It focuses on key deep learning (DL) frameworks, including convolutional neural networks (CNNs), recurrent neural networks (RNNs), and generative adversarial networks (GANs). The review examines their applications in important medical imaging tasks such as image classification, segmentation, reconstruction, and disease prediction. It also considers how DL techniques are integrated with tools like radiomics, data augmentation strategies, and predictive analytics models. DL methods have shown superior performance in detecting and classifying diseases like pneumonia, tuberculosis, and Alzheimer's. They also improve the quality and speed of imaging modalities such as MRI, CT, and ultrasound. Despite these advances, challenges remain in data availability, model interpretability, clinical validation, and ethical issues related to bias and privacy. Addressing these challenges is essential for the successful clinical use of DL in medical imaging. This review ends with suggestions for future directions and best practices for ethically and practically integrating DL technologies into routine healthcare.},
}

@article {pmid42392701,
year = {2026},
author = {Li, JY and Wang, XX and Wan, SF and Feng, TT and Guo, AJ and Liu, JY and Feng, K},
title = {[Research progress on role of PINK1/Parkin-mediated mitophagy in Alzheimer's disease and TCM interventions].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {8},
pages = {2143-2152},
doi = {10.19540/j.cnki.cjcmm.20260113.701},
pmid = {42392701},
issn = {1001-5302},
mesh = {Humans ; PTEN-Induced Putative Kinase ; *Protein Kinases/metabolism/genetics ; *Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Mitophagy/drug effects ; Animals ; *Drugs, Chinese Herbal/administration & dosage ; Mitochondria/metabolism/drug effects ; },
abstract = {Alzheimer's disease(AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Current treatment strategies mainly focus on symptomatic regulation of the neurotransmitter system, but their intervention effects on key pathological processes such as amyloid β(Aβ) deposition and abnormal phosphorylation of Tau protein remain limited. Therefore, it is urgent to explore new intervention targets from the perspective of the key mechanisms underlying the disease's occurrence and development. In recent years, mitochondrial dysfunction and imbalanced mitophagy have been recognized as closely related to the onset and progression of AD. The PTEN-induced putative kinase 1(PINK1)/E3 ubiquitin-protein ligase parkin(Parkin) pathway is a classic mechanism for the recognition, ubiquitination marking, and autophagic clearance of damaged mitochondria. Multiple studies have shown that under AD pathological conditions, the expression of this pathway is blocked, or its activity is reduced, leading to restricted mitophagy flux and obstacle clearance, which in turn exacerbate oxidative stress, energy metabolism disorders, and synaptic function damage, accelerating neuronal degeneration. Based on this, intervention strategies targeting PINK1/Parkin-mediated mitophagy have gradually attracted attention. Existing research indicates that single components and formulas of TCM, as well as some bioactive molecules, can reduce Aβ deposition, inhibit abnormal phosphorylation of Tau protein, and enhance synaptic plasticity by regulating PINK1/Parkin-mediated mitophagy, thereby exerting neuroprotective effects and improving cognitive function. However, the current evidence mainly comes from experimental studies, and the blood-brain barrier permeability, long-term safety, and clinical reproducibility of these interventions still need further verification. This article systematically reviewed the molecular mechanisms and upstream regulatory networks of PINK1/Parkin-mediated mitophagy, elaborated on the research evidence of its role in the pathological process of AD, and focused on summarizing the research progress of TCM interventions targeting this pathway, aiming to provide references for subsequent mechanism verification, evidence-based research design, and exploration of comprehensive intervention strategies.},
}

Humans
PTEN-Induced Putative Kinase
*Protein Kinases/metabolism/genetics
*Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology
*Ubiquitin-Protein Ligases/metabolism/genetics
*Mitophagy/drug effects
Animals
*Drugs, Chinese Herbal/administration & dosage
Mitochondria/metabolism/drug effects

@article {pmid42392719,
year = {2026},
author = {Yuan, CB and Ju, YT and Liu, YM and Wang, BS and Zhang, L and Yu, CY and Yang, YL and Chen, WY and Leng, YJ and Cheng, MJ and Min, DY},
title = {[Quercetin improves cognitive impairment in mice with Alzheimer's disease by inhibiting inflammatory response and activating cAMP/PKA/CREB signaling pathway].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {8},
pages = {2323-2334},
doi = {10.19540/j.cnki.cjcmm.20251210.801},
pmid = {42392719},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/immunology/psychology/metabolism ; Male ; *Quercetin/administration & dosage ; Signal Transduction/drug effects ; Mice ; *Cyclic AMP Response Element-Binding Protein/genetics/metabolism ; Humans ; *Cyclic AMP/metabolism/genetics/immunology ; *Cyclic AMP-Dependent Protein Kinases/genetics/metabolism ; Mice, Inbred C57BL ; *Cognitive Dysfunction/drug therapy/genetics ; Mice, Transgenic ; Disease Models, Animal ; Hippocampus/drug effects ; },
abstract = {This study aimed to investigate the effects of quercetin on cognitive dysfunction in a mouse model of Alzheimer's disease(AD) and to explore its potential mechanisms. Network pharmacology was used to construct a "drug-core component-key target-pathways-disease" network to identify potential targets and related pathways associated with drug efficacy. Thirty 3-month-old male APP/PS1 transgenic mice were randomly divided into a model group, a quercetin group(100 mg·kg~(-1)), and a donepezil hydrochloride group(0.5 mg·kg~(-1)), while age-matched C57BL/6J mice from the same litter served as the control group. Each group consisted of 10 mice, and the treatment groups received the corresponding drug interventions for 24 weeks. The Morris water maze(MWM) test was used to assess memory performance, and the nest-building test was applied to evaluate daily living ability. hematoxylin-eosin(HE) staining, Nissl staining, and immunohistochemistry were used to assess pathological changes in hippocampal neurons. Western blot analysis was used to detect the expression levels of tau, phosphorylated(p)-tau, interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), brain-derived neurotrophic factor(BDNF), cyclic adenosine monophosphate(cAMP), protein kinase A(PKA), p-PKA, cAMP response element-binding protein(CREB), and p-CREB-related signaling proteins in hippocampal tissue. Network pharmacology analysis identified 165 quercetin-related active component targets and 4 324 learning-and memory-related targets. Intersection analysis yielded 71 AD-related core genes. Protein-protein interaction(PPI) network analysis identified protein kinase B(Akt1), estrogen receptor 1(ESR1), epidermal growth factor receptor(EGFR), and non-receptor tyrosine kinase(SRC) as core target genes. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis indicated that quercetin may regulate AD progression through the PI3K/Akt signaling pathway, cAMP signaling pathway, TNF signaling pathway, and EGFR tyrosine kinase inhibitor resistance-related pathways. Animal experiments showed that, compared with the control group, the model group exhibited significantly reduced nesting scores, prolonged escape latency(P<0.05), and fewer platform crossings(P<0.05). The number of neurons in the cortex and hippocampus was significantly decreased, and extracellular amyloid β(Aβ) deposition was significantly increased(P<0.01). In addition, the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly elevated(P<0.01), whereas BDNF protein expression was significantly reduced(P<0.01). Compared with the model group, the quercetin and donepezil hydrochloride groups showed significantly increased nesting scores, shortened escape latency(P<0.05), and increased numbers of platform crossings(P<0.05). The number of neurons in the hippocampal CA1 region was significantly increased(P<0.01), and the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly decreased(P<0.05, P<0.01). These results indicate that quercetin can significantly improve cognitive impairment in APP/PS1 transgenic mice, and its mechanism may be associated with activation of the cAMP/PKA/CREB signaling pathway and reversal of the upregulation of pro-inflammatory cytokines, including TNF-α and IL-1β.},
}

Animals
*Alzheimer Disease/drug therapy/genetics/immunology/psychology/metabolism
Male
*Quercetin/administration & dosage
Signal Transduction/drug effects
Mice
*Cyclic AMP Response Element-Binding Protein/genetics/metabolism
Humans
*Cyclic AMP/metabolism/genetics/immunology
*Cyclic AMP-Dependent Protein Kinases/genetics/metabolism
Mice, Inbred C57BL
*Cognitive Dysfunction/drug therapy/genetics
Mice, Transgenic
Disease Models, Animal
Hippocampus/drug effects

@article {pmid42392731,
year = {2026},
author = {Lyu, SY and Wang, XZ and Chen, XY and Guo, R},
title = {[Exploring mechanism of "treating different diseases with the same method" for depression and Alzheimer's disease based on "liver-spleen-kidney" axis and advances in traditional Chinese medicine intervention].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {10},
pages = {2726-2738},
doi = {10.19540/j.cnki.cjcmm.20260108.302},
pmid = {42392731},
issn = {1001-5302},
mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology/metabolism ; *Drugs, Chinese Herbal/administration & dosage/therapeutic use ; *Spleen/drug effects/physiopathology ; *Kidney/drug effects/physiopathology ; *Liver/drug effects/physiopathology ; Animals ; *Medicine, Chinese Traditional ; *Depression/drug therapy/physiopathology ; },
abstract = {Depression(major depressive disorder, MDD) and Alzheimer's disease(AD) are two highly prevalent neuropsychiatric disorders. With the aging population, their comorbidity rate continues to rise. The pathogenesis of MDD and AD is complex, and modern medicine still lacks strategies that can simultaneously intervene in the core processes of both diseases. The theory of "treating different diseases with the same method" in traditional Chinese medicine(TCM) is an important therapeutic principle, which means that different diseases showing identical syndromes during their development can be treated with the same approach. This provides a TCM perspective for the diagnosis and treatment of their comorbidity. Based on the theory of the "liver-spleen-kidney" axis, this study identified that MDD and AD shared common pathogenesis: liver dysfunction in free coursing, spleen dysfunction in transportation, and kidney essence deficiency. It further connected this pathogenesis with the dysregulation of the neuroendocrine-immune(NEI) network in modern medicine, revealing common pathological mechanisms in neuroinflammation, dysfunction of the "hypothalamic-pituitary-adrenal"(HPA) axis, and gut microbiota dysbiosis. Meanwhile, it also reviewed specific mechanisms of TCM herbs such as Bupleuri Radix(Chaihu), Paeoniae Radix Alba(Baishao), and Astragali Radix(Huangqi), as well as their active components, in treating MDD and AD by regulating the NEI network through multiple targets and pathways. This may provide evidence for the application of the "treating different diseases with the same method" theory and broaden the perspective for the treatment of MDD and AD.},
}

Humans
*Alzheimer Disease/drug therapy/physiopathology/metabolism
*Drugs, Chinese Herbal/administration & dosage/therapeutic use
*Spleen/drug effects/physiopathology
*Kidney/drug effects/physiopathology
*Liver/drug effects/physiopathology
Animals
*Medicine, Chinese Traditional
*Depression/drug therapy/physiopathology

@article {pmid42381088,
year = {2026},
author = {Verberk, IMW and de Koning, LA and Coomans, EM and Trieu, C and Leeuwis, AE and Hunter, J and Honigberg, L and van der Flier, WM and Vijverberg, EGB and Ossenkoppele, R and van de Giessen, E and Teunissen, CE},
title = {The potential of key Alzheimer's plasma biomarkers to mimic tau PET MUBADA-based disease staging.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02085-6},
pmid = {42381088},
issn = {1758-9193},
abstract = {BACKGROUND: Patients with Alzheimer's disease (AD) with a low to intermediate tau-PET burden might benefit most from anti-amyloid treatment. Staging tau burden with plasma biomarkers would offer a scalable alternative to staging with tau-PET. This study investigated whether key plasma biomarkers P-tau217, P-tau181, Aβ42/40, GFAP and NfL can be used to accurately stage amyloid status (A-/A+) and tau-PET burden, and evaluated the relation of such a plasma-based staging system with cognitive outcomes over time.

METHODS: We included 105 participants with subjective cognitive decline (n = 27 A-, n = 18 A+), A+ mild cognitive impairment (n = 10) or A + AD-dementia (n = 50) from the Amsterdam Dementia Cohort who underwent [[18]F]flortaucipir PET-burden assessment (Tlow, Tintermediate or Thigh; based on MUBADA SUVr) and longitudinal cognitive assessment (average follow-up: 4.1 ± 3.5 years). AD-related plasma biomarkers were measured with Simoa. Discriminative performance (AUC) of each marker was compared using ROC analysis, and combined utility was assessed with logistic regression. Subsequently, cutoffs were established aiming for 90%-specificity, to regroup participants into a plasma-based staging scheme. Age-, sex- and education-adjusted linear mixed models (LMM) were performed to compare associations of plasma versus PET-based staging with longitudinal cognition.

RESULTS: 27 participants were A-TPET_low, 22 A+TPET_low, 27 A+TPET_int and 29 A+TPET_high. To discriminate A-TPET_low participants from A+TPET_low/int participants, P-tau217 performed best among all measured markers P-tau217, P-tau181, Aβ42/40, GFAP and NfL (AUC = 0.92 [95% CI: 0.856-0.985]). To discriminate A+TPET_high participants from A+TPET_low/int participants, also P-tau217 performed best among all markers (AUC = 0.74 [95% CI: 0.618-0.862]). A combination of Wald's backward-selected plasma markers did not statistically improve discriminative performance (DeLong's p > 0.05; two-marker combinations selected). Applying two cutoffs for P-tau217 as well as for the two-marker combinations, at 90% specificity to discriminate subsequent groups, we derived two plasma-based staging schemes. While the tau-PET staging scheme significantly and consistently associated with cognitive performance and decline across cognitive domains in LMMs, the plasma staging schemes did not.

CONCLUSIONS: Performance of plasma-based staging approaches developed in this study were high when discriminating individuals without amyloid pathology, while this was moderate when discriminating amyloid positive individuals with a high tau-PET burden. Our LMM findings visualize that tau staging in amyloid-positive individuals remains optimally performed with tau-PET scans.},
}

@article {pmid42381140,
year = {2026},
author = {Li, Y and Xie, K and Qian, S and Wang, Z and Zhang, H and Si, L},
title = {Quantifying Short-Term Functional Changes After Lecanemab Treatment in Early Alzheimer's Disease: An Exploratory 3-Month Follow-Up Case Report Using Eye Movement and Gait Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050471024260520113701},
pmid = {42381140},
issn = {1875-5828},
abstract = {INTRODUCTION: Lecanemab is a monoclonal antibody targeting amyloid-β (Aβ) and is currently used in clinical practice for the treatment of early Alzheimer's disease (AD). However, noninvasive biomarkers reflecting its early efficacy are still unclear. This exploratory case report aims to investigate the combination of eye movement and gait analysis to quantitatively monitor shortterm functional changes during lecanemab treatment.

CASE PRESENTATION: Two male patients, both diagnosed with mild Alzheimer's disease through amyloid- PET and both with the APOE ε3/ε3 genotype, received intravenous lecanemab (10 mg/kg, every two weeks) for three months. Cognitive assessments (Montreal Cognitive Assessment, Mini- Mental State Examination, Clinical Dementia Rating), eye movement tests (smooth pursuit, overlapping saccades, anti-saccades), and gait analysis under single-task and dual-task conditions were conducted at baseline and follow-up. Patient 1 (79 years old) showed stable cognitive function, significant improvement in multiple eye movement parameters, and partial improvement in gait under single-task conditions. Patient 2 (60 years old) did not follow up on cognitive function tests as scheduled and showed inconsistent changes in eye movement parameters, but improved selected gait measures under dual-task conditions, particularly a shorter turning time. Neither patient experienced Amyloid-Related Imaging Abnormalities or infusion-related adverse events during the infusion process.

CONCLUSION: This exploratory case report suggests that eye movement and gait analysis may be sensitive to short-term functional changes following lecanemab treatment, which were not consistently captured by traditional cognitive scales. These findings are hypothesis-generating and warrant further investigation in larger studies. Multimodal functional assessment may hold promise as a tool for monitoring early treatment effects in Alzheimer's disease.},
}

@article {pmid42381141,
year = {2026},
author = {Mehrabadi, S},
title = {The Role of Digital Health Technologies in Early Detection and Management of Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050415800251226061142},
pmid = {42381141},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and functional impairment, posing significant challenges for early detection and management. In recent years, digital health technologies have emerged as promising tools to enhance the diagnosis, monitoring, and treatment of AD. This review paper explores the multifaceted role of digital health technologies in the early detection and management of Alzheimer's disease. We examine the use of wearable devices that monitor cognitive function and daily activities, as well as mobile health applications designed for cognitive training and symptom tracking. Additionally, we analyze the impact of telehealth services in providing remote care, particularly for underserved populations. The integration of artificial intelligence and machine learning for analyzing behavioral and cognitive data to support early diagnosis and risk assessment is also discussed. Furthermore, we explore the concept of digital biomarkers and their potential to complement traditional diagnostic methods. Ethical considerations surrounding privacy, data security, and informed consent are addressed to ensure responsible implementation of these technologies. Finally, we highlight gaps in current research and propose future directions for integrating digital health technologies into Alzheimer's care, emphasizing the potential for personalized interventions tailored to individual patient needs. This review underscores the transformative potential of digital health to reshape Alzheimer's disease management and improve patient outcomes.},
}

@article {pmid42382036,
year = {2026},
author = {Hofmann, A and Paczynski, M and Ponisio, MR and Saef, B and Roberts, JP and Powell, WJB and Gupta, A and Oh, I and Hofford, M and Posey, Z and Aldinger, M and Benzinger, TLS and Morris, JC and Snider, BJ and Schindler, SE},
title = {Performing multiple biomarker tests delays initiation of amyloid-targeting treatments.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70387},
pmid = {42382036},
issn = {2352-8729},
abstract = {INTRODUCTION: With the clinical availability of amyloid-targeting treatments (ATTs), accurate and timely biomarker-based diagnosis of Alzheimer's disease (AD) has become increasingly important. Three AD biomarker modalities are commonly available in clinical practice: amyloid positron emission tomography (PET), cerebrospinal fluid (CSF) tests, and blood tests.

METHODS: We investigated the use and agreement of different biomarker modalities in a memory clinic. Further, we calculated the time until ATT initiation for patients who underwent a single test versus multiple biomarker tests.

RESULTS: The blood test agreed with amyloid PET in nine of 11 patients and CSF tests in all 14 patients. The median time from first clinic visit to ATT initiation was 4.7 months in 209 patients who underwent a single test and 8.1 months in 12 patients who underwent multiple tests.

DISCUSSION: Performing multiple biomarker tests delays initiation of ATT and should be restricted to patients with uncertain amyloid status following the first biomarker test.},
}

@article {pmid42382677,
year = {2026},
author = {Siam, NH and Nasrin, N and Saiyara, S and Saha, H and Deb, DP and Islam, J},
title = {Medicinal Plants and Their Bioactive Phytochemicals as Emerging Therapeutic Strategies for Alzheimer's Disease: An Integrative Review of Preclinical and Clinical Evidence.},
journal = {Scientifica},
volume = {2026},
number = {},
pages = {6124916},
pmid = {42382677},
issn = {2090-908X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid deposition, tau hyperphosphorylation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and blood-brain barrier disruption, collectively leading to widespread cortical and subcortical atrophy. Current FDA-approved pharmacotherapies, including acetylcholinesterase inhibitors and memantine, provide only modest symptomatic relief and fail to halt disease progression, underscoring the urgent need for alternative therapeutic approaches. Growing evidence highlights medicinal plants and their bioactive phytoconstituents as promising candidates for AD prevention and treatment because of their multitarget mechanisms, favorable safety profiles, and long history of traditional use. This review synthesizes extensive in vitro, in vivo, and clinical studies demonstrating the neuroprotective potential of plant extracts and isolated compounds that exert antioxidant, anti-inflammatory, antiamyloidogenic, anti-tau, cholinesterase-inhibitory, and synaptic-modulating effects. Key medicinal species, including Abelmoschus esculentus, Brassica oleracea, Cannabis sativa, Citrus reticulata, Lantana camara, Launaea taraxacifolia, Lawsonia inermis, Marrubium vulgare, Markhamia lutea, Persicaria minor, Pithecellobium dulce, Salvia aristata, Trigonella foenum-graecum, and Withania somnifera, show significant cognitive and neuroprotective benefits in experimental AD models. Phytochemicals such as sulforaphane, nobiletin, trigonelline, diosgenin, verbascoside, withaferin A, and withanolides strongly modulate the amyloid, tau, oxidative, and inflammatory pathways. Clinical trials further support the therapeutic potential of several plant-derived interventions for mild cognitive impairment and AD-related dementia. Collectively, these findings highlight medicinal plants and their active constituents as compelling complementary or translational strategies for AD management, warranting further mechanistic and clinical validation. This review aims to evaluate the neuroprotective potential of medicinal plants and their bioactive compounds in preventing and managing AD by summarizing evidence from in vitro, in vivo, and clinical studies.},
}